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Issue published July 8, 2021

  • Volume 6, Issue 13
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  • Research Articles
  • Review
COVID-19 and rheumatoid arthritis share tissue macrophage clusters expressing the proinflammatory mediator SPP1

MacDonald et al. find that COVID-19 pneumonitis appears to be driven by pathogenic myeloid cell pathways similar to those in rheumatoid arthritis; and that macrophages expressing the inflammatory mediator osteopontin (SPP1) activate PD-L1+ neutrophils and classical monocytes. The cover image shows SPP1+ macrophages in alveoli in a COVID-19 postmortem lung, with immunostaining for SPP1 (green) and the macrophage marker CD68 (red). Nuclei were stained with DAPI (blue).

Review
Cardiovascular complications of COVID-19
Farnaz Farshidfar, … , Navid Koleini, Hossein Ardehali
Farnaz Farshidfar, … , Navid Koleini, Hossein Ardehali
Published June 1, 2021
Citation Information: JCI Insight. 2021;6(13):e148980. https://doi.org/10.1172/jci.insight.148980.
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Cardiovascular complications of COVID-19

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Abstract

The emergence of the novel SARS coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has resulted in an unprecedented pandemic that has been accompanied by a global health crisis. Although the lungs are the main organs involved in COVID-19, systemic disease with a wide range of clinical manifestations also develops in patients infected with SARS-CoV-2. One of the major systems affected by this virus is the cardiovascular system. The presence of preexisting cardiovascular disease increases mortality in patients with COVID-19, and cardiovascular injuries, including myocarditis, cardiac rhythm abnormalities, endothelial cell injury, thrombotic events, and myocardial interstitial fibrosis, are observed in some patients with COVID-19. The underlying pathophysiology of COVID-19–associated cardiovascular complications is not fully understood, although direct viral infection of myocardium and cytokine storm have been suggested as possible mechanisms of myocarditis. In this Review, we summarize available data on SARS-CoV-2–related cardiac damage and discuss potential mechanisms of cardiovascular implications of this rapidly spreading virus.

Authors

Farnaz Farshidfar, Navid Koleini, Hossein Ardehali

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Research Articles
JunD, not c-Jun, is the AP-1 transcription factor required for Ras-induced lung cancer
E. Josue Ruiz, … , Julian Downward, Axel Behrens
E. Josue Ruiz, … , Julian Downward, Axel Behrens
Published July 8, 2021
Citation Information: JCI Insight. 2021;6(13):e124985. https://doi.org/10.1172/jci.insight.124985.
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JunD, not c-Jun, is the AP-1 transcription factor required for Ras-induced lung cancer

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Abstract

The AP-1 transcription factor c-Jun is required for Ras-driven tumorigenesis in many tissues and is considered as a classical proto-oncogene. To determine the requirement for c-Jun in a mouse model of K-RasG12D–induced lung adenocarcinoma, we inducibly deleted c-Jun in the adult lung. Surprisingly, we found that inactivation of c-Jun, or mutation of its JNK phosphorylation sites, actually increased lung tumor burden. Mechanistically, we found that protein levels of the Jun family member JunD were increased in the absence of c-Jun. In c-Jun–deficient cells, JunD phosphorylation was increased, and expression of a dominant-active JNKK2-JNK1 transgene further increased lung tumor formation. Strikingly, deletion of JunD completely abolished Ras-driven lung tumorigenesis. This work identifies JunD, not c-Jun, as the crucial substrate of JNK signaling and oncogene required for Ras-induced lung cancer.

Authors

E. Josue Ruiz, Linxiang Lan, Markus Elmar Diefenbacher, Eva Madi Riising, Clive Da Costa, Atanu Chakraborty, Joerg D. Hoeck, Bradley Spencer-Dene, Gavin Kelly, Jean-Pierre David, Emma Nye, Julian Downward, Axel Behrens

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Zebrafish mutants provide insights into Apolipoprotein B functions during embryonic development and pathological conditions
Hanoch Templehof, … , Inbal Avraham-Davidi, Karina Yaniv
Hanoch Templehof, … , Inbal Avraham-Davidi, Karina Yaniv
Published July 8, 2021
Citation Information: JCI Insight. 2021;6(13):e130399. https://doi.org/10.1172/jci.insight.130399.
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Zebrafish mutants provide insights into Apolipoprotein B functions during embryonic development and pathological conditions

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Abstract

Apolipoprotein B (ApoB) is the primary protein of chylomicrons, VLDLs, and LDLs and is essential for their production. Defects in ApoB synthesis and secretion result in several human diseases, including abetalipoproteinemia and familial hypobetalipoproteinemia (FHBL1). In addition, ApoB-related dyslipidemia is linked to nonalcoholic fatty liver disease (NAFLD), a silent pandemic affecting billions globally. Due to the crucial role of APOB in supplying nutrients to the developing embryo, ApoB deletion in mammals is embryonic lethal. Thus, a clear understanding of the roles of this protein during development is lacking. Here, we established zebrafish mutants for 2 apoB genes: apoBa and apoBb.1. Double-mutant embryos displayed hepatic steatosis, a common hallmark of FHBL1 and NAFLD, as well as abnormal liver laterality, decreased numbers of goblet cells in the gut, and impaired angiogenesis. We further used these mutants to identify the domains within ApoB responsible for its functions. By assessing the ability of different truncated forms of human APOB to rescue the mutant phenotypes, we demonstrate the benefits of this model for prospective therapeutic screens. Overall, these zebrafish models uncover what are likely previously undescribed functions of ApoB in organ development and morphogenesis and shed light on the mechanisms underlying hypolipidemia-related diseases.

Authors

Hanoch Templehof, Noga Moshe, Inbal Avraham-Davidi, Karina Yaniv

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A KCNK16 mutation causing TALK-1 gain of function is associated with maturity-onset diabetes of the young
Sarah M. Graff, … , David A. Jacobson, Emma L. Duncan
Sarah M. Graff, … , David A. Jacobson, Emma L. Duncan
Published May 25, 2021
Citation Information: JCI Insight. 2021;6(13):e138057. https://doi.org/10.1172/jci.insight.138057.
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A KCNK16 mutation causing TALK-1 gain of function is associated with maturity-onset diabetes of the young

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Abstract

Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic disorders of impaired pancreatic β cell function. The mechanisms underlying MODY include β cell KATP channel dysfunction (e.g., KCNJ11 [MODY13] or ABCC8 [MODY12] mutations); however, no other β cell channelopathies have been associated with MODY to date. Here, we have identified a nonsynonymous coding variant in KCNK16 (NM_001135105: c.341T>C, p.Leu114Pro) segregating with MODY. KCNK16 is the most abundant and β cell–restricted K+ channel transcript, encoding the two-pore-domain K+ channel TALK-1. Whole-cell K+ currents demonstrated a large gain of function with TALK-1 Leu114Pro compared with TALK-1 WT, due to greater single-channel activity. Glucose-stimulated membrane potential depolarization and Ca2+ influx were inhibited in mouse islets expressing TALK-1 Leu114Pro with less endoplasmic reticulum Ca2+ storage. TALK-1 Leu114Pro significantly blunted glucose-stimulated insulin secretion compared with TALK-1 WT in mouse and human islets. These data suggest that KCNK16 is a previously unreported gene for MODY.

Authors

Sarah M. Graff, Stephanie R. Johnson, Paul J. Leo, Prasanna K. Dadi, Matthew T. Dickerson, Arya Y. Nakhe, Aideen M. McInerney-Leo, Mhairi Marshall, Karolina E. Zaborska, Charles M. Schaub, Matthew A. Brown, David A. Jacobson, Emma L. Duncan

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Identification of antigen-specific TCR sequences based on biological and statistical enrichment in unselected individuals
Neal P. Smith, … , J. Christopher Love, Wayne G. Shreffler
Neal P. Smith, … , J. Christopher Love, Wayne G. Shreffler
Published May 25, 2021
Citation Information: JCI Insight. 2021;6(13):e140028. https://doi.org/10.1172/jci.insight.140028.
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Identification of antigen-specific TCR sequences based on biological and statistical enrichment in unselected individuals

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Abstract

Recent advances in high-throughput T cell receptor (TCR) sequencing have allowed for new insights into the human TCR repertoire. However, methods for capturing antigen-specific repertoires remain an area of development. Here, we describe a potentially novel approach that utilizes both a biological and statistical enrichment to define putatively antigen-specific complementarity-determining region 3 (CDR3) repertoires in unselected individuals. The biological enrichment entailed FACS of in vitro antigen-activated memory CD4+ T cells, followed by TCRβ sequencing. The resulting TCRβ sequences were then filtered by selecting those that are statistically enriched when compared with their frequency in the autologous resting T cell compartment. Applying this method to define putatively peanut protein–specific repertoires in 27 peanut-allergic individuals resulted in a library of 7345 unique CDR3β amino acid sequences that had similar characteristics to other validated antigen-specific repertoires in terms of homology and diversity. In-depth analysis of these CDR3βs revealed 36 public sequences that demonstrated high levels of convergent recombination. In a network analysis, the public CDR3βs were shown to be core sequences with more edges than their private counterparts. This method has the potential to be applied to a wide range of T cell–mediated disorders and to yield new biomarkers and biological insights.

Authors

Neal P. Smith, Bert Ruiter, Yamini V. Virkud, Ang A. Tu, Brinda Monian, James J. Moon, J. Christopher Love, Wayne G. Shreffler

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Natural killer cells and cytotoxic T lymphocytes are required to clear solid tumor in a patient-derived xenograft
Duy Tri Le, … , John J. Tyner, Silke Paust
Duy Tri Le, … , John J. Tyner, Silke Paust
Published June 3, 2021
Citation Information: JCI Insight. ;6(13):e140116. https://doi.org/10.1172/jci.insight.140116.
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Natural killer cells and cytotoxic T lymphocytes are required to clear solid tumor in a patient-derived xenograft

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Abstract

Existing patient-derived xenograft (PDX) mouse models of solid tumors lack a fully tumor donor–matched, syngeneic, and functional immune system. We developed a model that overcomes these limitations by engrafting lymphopenic recipient mice with a fresh, undisrupted piece of solid tumor, whereby tumor-infiltrating lymphocytes (TILs) persisted in the recipient mice for several weeks. Successful tumor engraftment was achieved in 83% to 89% of TIL-PDX mice, and these were seen to harbor exhausted immuno-effector as well as functional immunoregulatory cells persisting for at least 6 months postengraftment. Combined treatment with interleukin-15 stimulation and immune checkpoint inhibition resulted in complete or partial tumor response in this model. Further, depletion of cytotoxic T lymphocytes and/or natural killer cells before combined immunotherapy revealed that both cell types were required for maximal tumor regression. Our TIL-PDX model provides a valuable resource for powerful mechanistic and therapeutic studies in solid tumors.

Authors

Duy Tri Le, Tridu R. Huynh, Bryan Burt, George Van Buren, Shawn A. Abeynaike, Cristina Zalfa, Rana Nikzad, Farrah Kheradmand, John J. Tyner, Silke Paust

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Ferritin H deficiency deteriorates cellular iron handling and worsens Salmonella typhimurium infection by triggering hyperinflammation
David Haschka, … , Igor Theurl, Guenter Weiss
David Haschka, … , Igor Theurl, Guenter Weiss
Published July 8, 2021
Citation Information: JCI Insight. 2021;6(13):e141760. https://doi.org/10.1172/jci.insight.141760.
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Ferritin H deficiency deteriorates cellular iron handling and worsens Salmonella typhimurium infection by triggering hyperinflammation

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Abstract

Iron is an essential nutrient for mammals as well as for pathogens. Inflammation-driven changes in systemic and cellular iron homeostasis are central for host-mediated antimicrobial strategies. Here, we studied the role of the iron storage protein ferritin H (FTH) for the control of infections with the intracellular pathogen Salmonella enterica serovar Typhimurium by macrophages. Mice lacking FTH in the myeloid lineage (LysM-Cre+/+Fthfl/fl mice) displayed impaired iron storage capacities in the tissue leukocyte compartment, increased levels of labile iron in macrophages, and an accelerated macrophage-mediated iron turnover. While under steady-state conditions, LysM-Cre+/+Fth+/+ and LysM-Cre+/+Fthfl/fl animals showed comparable susceptibility to Salmonella infection, i.v. iron supplementation drastically shortened survival of LysM-Cre+/+Fthfl/fl mice. Mechanistically, these animals displayed increased bacterial burden, which contributed to uncontrolled triggering of NF-κB and inflammasome signaling and development of cytokine storm and death. Importantly, pharmacologic inhibition of the inflammasome and IL-1β pathways reduced cytokine levels and mortality and partly restored infection control in iron-treated ferritin-deficient mice. These findings uncover incompletely characterized roles of ferritin and cellular iron turnover in myeloid cells in controlling bacterial spread and for modulating NF-κB and inflammasome-mediated cytokine activation, which may be of vital importance in iron-overloaded individuals suffering from severe infections and sepsis.

Authors

David Haschka, Piotr Tymoszuk, Verena Petzer, Richard Hilbe, Simon Heeke, Stefanie Dichtl, Sergej Skvortsov, Egon Demetz, Sylvia Berger, Markus Seifert, Anna-Maria Mitterstiller, Patrizia Moser, Dirk Bumann, Manfred Nairz, Igor Theurl, Guenter Weiss

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ACTH treatment promotes murine cardiac allograft acceptance
Jing Zhao, … , Vivek Kasinath, Reza Abdi
Jing Zhao, … , Vivek Kasinath, Reza Abdi
Published July 8, 2021
Citation Information: JCI Insight. 2021;6(13):e143385. https://doi.org/10.1172/jci.insight.143385.
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ACTH treatment promotes murine cardiac allograft acceptance

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Abstract

Heart transplantation is the optimal therapy for patients with end-stage heart disease, but its long-term outcome remains inadequate. Recent studies have highlighted the importance of the melanocortin receptors (MCRs) in inflammation, but how MCRs regulate the balance between alloreactive T cells and Tregs, and whether they impact chronic heart transplant rejection, is unknown. Here, we found that Tregs express MC2R, and MC2R expression was highest among all MCRs by Tregs. Our data indicate that adrenocorticotropic hormone (ACTH), the sole ligand for MC2R, promoted the formation of Tregs by increasing the expression of IL-2Rα (CD25) in CD4+ T cells and activation of STAT5 in CD4+CD25+ T cells. ACTH treatment also improved the survival of heart allografts and increased the formation of Tregs in CD28KO mice. ACTH treatment synergized with the tolerogenic effect of CTLA-4–Ig, resulting in long-term survival of heart allografts and an increase in intragraft Tregs. ACTH administration also demonstrated higher prolongation of heart allograft survival in transgenic mouse recipients with both complete KO and conditional KO of PI3Kγ in T cells. Finally, ACTH treatment reduced chronic rejection markedly. These data demonstrate that ACTH treatment improved heart transplant outcomes, and this effect correlated with an increase in Tregs.

Authors

Jing Zhao, Liwei Jiang, Mayuko Uehara, Naima Banouni, Basmah S. Al Dulaijan, Jamil Azzi, Takaharu Ichimura, Xiaofei Li, Petr Jarolim, Paolo Fiorina, Stefan G. Tullius, Joren C. Madsen, Vivek Kasinath, Reza Abdi

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Imaging alloreactive T cells provides early warning of organ transplant rejection
Toshihito Hirai, … , Robert S. Negrin, Sanjiv S. Gambhir
Toshihito Hirai, … , Robert S. Negrin, Sanjiv S. Gambhir
Published July 8, 2021
Citation Information: JCI Insight. ;6(13):e145360. https://doi.org/10.1172/jci.insight.145360.
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Imaging alloreactive T cells provides early warning of organ transplant rejection

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Abstract

Diagnosis of organ transplant rejection relies upon biopsy approaches to confirm alloreactive T cell infiltration in the graft. Immune molecular monitoring is under investigation to screen for rejection, though these techniques have suffered from low specificity and lack of spatial information. ImmunoPET utilizing antibodies conjugated to radioisotopes has the potential to improve early and accurate detection of graft rejection. ImmunoPET is capable of noninvasively visualizing the dynamic distribution of cells expressing specific immune markers in the entire body over time. In this work, we identify and characterize OX40 as a surrogate biomarker for alloreactive T cells in organ transplant rejection and monitor its expression by utilizing immunoPET. In a dual murine heart transplant model that has both syngeneic and allogeneic hearts engrafted in bilateral ear pinna on the recipients, OX40 immunoPET clearly depicted alloreactive T cells in the allograft and draining lymph node that were not observed in their respective isograft counterparts. OX40 immunoPET signals also reflected the subject’s immunosuppression level with tacrolimus in this study. OX40 immunoPET is a promising approach that may bridge molecular monitoring and morphological assessment for improved transplant rejection diagnosis.

Authors

Toshihito Hirai, Aaron T. Mayer, Tomomi W. Nobashi, Po-Yu Lin, Zunyu Xiao, Tomokatsu Udagawa, Kinya Seo, Federico Simonetta, Jeanette Baker, Alan G. Cheng, Robert S. Negrin, Sanjiv S. Gambhir

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TP53-mediated therapy-related clonal hematopoiesis contributes to doxorubicin-induced cardiomyopathy by augmenting a neutrophil-mediated cytotoxic response
Soichi Sano, … , Heather Doviak, Kenneth Walsh
Soichi Sano, … , Heather Doviak, Kenneth Walsh
Published July 8, 2021
Citation Information: JCI Insight. 2021;6(13):e146076. https://doi.org/10.1172/jci.insight.146076.
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TP53-mediated therapy-related clonal hematopoiesis contributes to doxorubicin-induced cardiomyopathy by augmenting a neutrophil-mediated cytotoxic response

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Abstract

Therapy-related clonal hematopoiesis (t-CH) is often observed in cancer survivors. This form of clonal hematopoiesis typically involves somatic mutations in driver genes that encode components of the DNA damage response and confer hematopoietic stem and progenitor cells (HSPCs) with resistance to the genotoxic stress of the cancer therapy. Here, we established a model of TP53-mediated t-CH through the transfer of Trp53 mutant HSPCs to mice, followed by treatment with a course of the chemotherapeutic agent doxorubicin. These studies revealed that neutrophil infiltration in the heart significantly contributes to doxorubicin-induced cardiac toxicity and that this condition is amplified in the model of Trp53-mediated t-CH. These data suggest that t-CH could contribute to the elevated heart failure risk that occurs in cancer survivors who have been treated with genotoxic agents.

Authors

Soichi Sano, Ying Wang, Hayato Ogawa, Keita Horitani, Miho Sano, Ariel H. Polizio, Anupreet Kour, Yoshimitsu Yura, Heather Doviak, Kenneth Walsh

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Maternal metabolic health drives mesenchymal stem cell metabolism and infant fat mass at birth
Melissa L. Erickson, … , Leanne M. Redman, Kristen E. Boyle
Melissa L. Erickson, … , Leanne M. Redman, Kristen E. Boyle
Published June 1, 2021
Citation Information: JCI Insight. 2021;6(13):e146606. https://doi.org/10.1172/jci.insight.146606.
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Maternal metabolic health drives mesenchymal stem cell metabolism and infant fat mass at birth

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Exposure to maternal obesity may promote metabolic dysfunction in offspring. We used infant mesenchymal stem cells (MSCs) to experimentally examine cellular mechanisms of intergenerational health transmission. Our earlier reports show MSCs collected from infants of mothers with obesity had a dichotomous distribution in metabolic efficiency; they were either efficient (Ef-Ob) or inefficient (In-Ob) with respect to fatty acid oxidation (FAO). Here, we sought to determine if this was due to a primary defect in FAO. Accordingly, we measured FAO in myogenic differentiating MSCs under 3 conditions: (a) myogenesis alone, (b) excess fatty acid exposure, and (c) excess fatty acid exposure plus a chemical uncoupler to increase metabolic rate. Compared with normal weight and Ef-Ob MSCs, In-Ob displayed lower FAO in myogenesis alone and after fatty acid plus uncoupler, indicating In-Ob were less metabolically flexible after increasing lipid availability and metabolic rate, demonstrating a primary deficit in FAO. MSC FAO was negatively associated with fasting maternal glucose and insulin and positively associated with fasting HDL-cholesterol. MSC FAO was negatively associated with infant fat mass. These data indicate a less favorable maternal metabolic milieu, independent of maternal BMI, reduces intrinsic MSC FAO and is linked to higher infant adiposity as early as birth.

Authors

Melissa L. Erickson, Zachary W. Patinkin, Allison M. Duensing, Dana Dabelea, Leanne M. Redman, Kristen E. Boyle

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Effect of sex chromosomes versus hormones in neonatal lung injury
Sandra L. Grimm, … , Cristian Coarfa, Krithika Lingappan
Sandra L. Grimm, … , Cristian Coarfa, Krithika Lingappan
Published June 1, 2021
Citation Information: JCI Insight. 2021;6(13):e146863. https://doi.org/10.1172/jci.insight.146863.
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Effect of sex chromosomes versus hormones in neonatal lung injury

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Abstract

The main mechanisms underlying sexually dimorphic outcomes in neonatal lung injury are unknown. We tested the hypothesis that hormone- or sex chromosome–mediated mechanisms interact with hyperoxia exposure to impact injury and repair in the neonatal lung. To distinguish sex differences caused by gonadal hormones versus sex chromosome complement (XX versus XY), we used the Four Core Genotypes (FCG) mice and exposed them to hyperoxia (95% FiO2, P1–P4: saccular stage) or room air. This model generates XX and XY mice that each have either testes (with Sry, XXM, or XYM) or ovaries (without Sry, XXF, or XYF). Lung alveolarization and vascular development were more severely impacted in XYM and XYF compared with XXF and XXM mice. Cell cycle–related pathways were enriched in the gonadal or chromosomal females, while muscle-related pathways were enriched in the gonadal males, and immune-response–related pathways were enriched in chromosomal males. Female gene signatures showed a negative correlation with human patients who developed bronchopulmonary dysplasia (BPD) or needed oxygen therapy at 28 days. These results demonstrate that chromosomal sex — and not gonadal sex — impacted the response to neonatal hyperoxia exposure. The female sex chromosomal complement was protective and could mediate sex-specific differences in the neonatal lung injury.

Authors

Sandra L. Grimm, Xiaoyu Dong, Yuhao Zhang, Alexandre F. Carisey, Arthur P. Arnold, Bhagavatula Moorthy, Cristian Coarfa, Krithika Lingappan

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COVID-19 and RA share an SPP1 myeloid pathway that drives PD-L1+ neutrophils and CD14+ monocytes
Lucy MacDonald, … , Mariola Kurowska-Stolarska, Elisa Gremese
Lucy MacDonald, … , Mariola Kurowska-Stolarska, Elisa Gremese
Published June 18, 2021
Citation Information: JCI Insight. 2021;6(13):e147413. https://doi.org/10.1172/jci.insight.147413.
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COVID-19 and RA share an SPP1 myeloid pathway that drives PD-L1+ neutrophils and CD14+ monocytes

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Abstract

We explored the potential link between chronic inflammatory arthritis and COVID-19 pathogenic and resolving macrophage pathways and their role in COVID-19 pathogenesis. We found that bronchoalveolar lavage fluid (BALF) macrophage clusters FCN1+ and FCN1+SPP1+ predominant in severe COVID-19 were transcriptionally related to synovial tissue macrophage (STM) clusters CD48hiS100A12+ and CD48+SPP1+ that drive rheumatoid arthritis (RA) synovitis. BALF macrophage cluster FABP4+ predominant in healthy lung was transcriptionally related to STM cluster TREM2+ that governs resolution of synovitis in RA remission. Plasma concentrations of SPP1 and S100A12 (key products of macrophage clusters shared with active RA) were high in severe COVID-19 and predicted the need for Intensive Care Unit transfer, and they remained high in the post–COVID-19 stage. High plasma levels of SPP1 were unique to severe COVID-19 when compared with other causes of severe pneumonia, and IHC localized SPP1+ macrophages in the alveoli of COVID-19 lung. Investigation into SPP1 mechanisms of action revealed that it drives proinflammatory activation of CD14+ monocytes and development of PD-L1+ neutrophils, both hallmarks of severe COVID-19. In summary, COVID-19 pneumonitis appears driven by similar pathogenic myeloid cell pathways as those in RA, and their mediators such as SPP1 might be an upstream activator of the aberrant innate response in severe COVID-19 and predictive of disease trajectory including post–COVID-19 pathology.

Authors

Lucy MacDonald, Stefano Alivernini, Barbara Tolusso, Aziza Elmesmari, Domenico Somma, Simone Perniola, Annamaria Paglionico, Luca Petricca, Silvia L. Bosello, Angelo Carfì, Michela Sali, Egidio Stigliano, Antonella Cingolani, Rita Murri, Vincenzo Arena, Massimo Fantoni, Massimo Antonelli, Francesco Landi, Francesco Franceschi, Maurizio Sanguinetti, Iain B. McInnes, Charles McSharry, Antonio Gasbarrini, Thomas D. Otto, Mariola Kurowska-Stolarska, Elisa Gremese

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RTEC-intrinsic IL-17–driven inflammatory circuit amplifies antibody-induced glomerulonephritis and is constrained by Regnase-1
De-Dong Li, … , Sarah L. Gaffen, Partha S. Biswas
De-Dong Li, … , Sarah L. Gaffen, Partha S. Biswas
Published July 8, 2021
Citation Information: JCI Insight. 2021;6(13):e147505. https://doi.org/10.1172/jci.insight.147505.
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RTEC-intrinsic IL-17–driven inflammatory circuit amplifies antibody-induced glomerulonephritis and is constrained by Regnase-1

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Abstract

Antibody-mediated glomerulonephritis (AGN) is a clinical manifestation of many autoimmune kidney diseases for which few effective treatments exist. Chronic inflammatory circuits in renal glomerular and tubular cells lead to tissue damage in AGN. These cells are targeted by the cytokine IL-17, which has recently been shown to be a central driver of the pathogenesis of AGN. However, surprisingly little is known about the regulation of pathogenic IL-17 signaling in the kidney. Here, using a well-characterized mouse model of AGN, we show that IL-17 signaling in renal tubular epithelial cells (RTECs) is necessary for AGN development. We also show that Regnase-1, an RNA binding protein with endoribonuclease activity, is a negative regulator of IL-17 signaling in RTECs. Accordingly, mice with a selective Regnase-1 deficiency in RTECs exhibited exacerbated kidney dysfunction in AGN. Mechanistically, Regnase-1 inhibits IL-17–driven expression of the transcription factor IκBξ and, consequently, its downstream gene targets, including Il6 and Lcn2. Moreover, deletion of Regnase-1 in human RTECs reduced inflammatory gene expression in a IκBξ-dependent manner. Overall, these data identify an IL-17–driven inflammatory circuit in RTECs during AGN that is constrained by Regnase-1.

Authors

De-Dong Li, Rami Bechara, Kritika Ramani, Chetan V. Jawale, Yang Li, Jay K. Kolls, Sarah L. Gaffen, Partha S. Biswas

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Reduced thyroxine production in young household contacts of tuberculosis patients increases active tuberculosis disease risk
Kamakshi Prudhula Devalraju, … , Vijaya Lakshmi Valluri, Ramakrishna Vankayalapati
Kamakshi Prudhula Devalraju, … , Vijaya Lakshmi Valluri, Ramakrishna Vankayalapati
Published July 8, 2021
Citation Information: JCI Insight. 2021;6(13):e148271. https://doi.org/10.1172/jci.insight.148271.
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Reduced thyroxine production in young household contacts of tuberculosis patients increases active tuberculosis disease risk

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Abstract

In the current study, we followed 839 household contacts (HHCs) of tuberculosis (TB) patients for 2 years and identified the factors that enhanced the development of TB. Fourteen of the 17 HHCs who progressed to TB were in the 15- to 30-year-old age group. At baseline (the “0“ time point, when all the individuals were healthy), the concentration of the thyroid hormone thyroxine (T4) was lower, and there were increased numbers of Tregs in PBMCs of TB progressors. At baseline, PBMCs from TB progressors stimulated with early secretory antigenic target 6 (ESAT-6) and 10 kDa culture filtrate antigen (CFP-10) produced less IL-1α. Thyroid hormones inhibited Mycobacterium tuberculosis (Mtb) growth in macrophages in an IL-1α–dependent manner. Mtb-infected Thra1PV/+ (mutant thyroid hormone receptor) mice had increased mortality and reduced IL-1α production. Our findings suggest that young HHCs who exhibit decreased production of thyroid hormones are at high risk of developing active TB disease.

Authors

Kamakshi Prudhula Devalraju, Deepak Tripathi, Venkata Sanjeev Kumar Neela, Padmaja Paidipally, Rajesh Kumar Radhakrishnan, Karan P. Singh, Mohammad Soheb Ansari, Martin Jaeger, Romana T. Netea-Maier, Mihai G. Netea, Sunmi Park, Sheue-yann Cheng, Vijaya Lakshmi Valluri, Ramakrishna Vankayalapati

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Recipient myeloperoxidase-producing cells regulate antibody-mediated acute versus chronic kidney allograft rejection
Satoshi Miyairi, … , Stanley L. Hazen, Robert L. Fairchild
Satoshi Miyairi, … , Stanley L. Hazen, Robert L. Fairchild
Published June 3, 2021
Citation Information: JCI Insight. 2021;6(13):e148747. https://doi.org/10.1172/jci.insight.148747.
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Recipient myeloperoxidase-producing cells regulate antibody-mediated acute versus chronic kidney allograft rejection

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Abstract

Antibody-mediated rejection (ABMR) continues to be a major problem undermining the success of kidney transplantation. Acute ABMR of kidney grafts is characterized by neutrophil and monocyte margination in the tubular capillaries and by graft transcripts indicating NK cell activation, but the myeloid cell mechanisms required for acute ABMR have remained unclear. Dysregulated donor-specific antibody (DSA) responses with high antibody titers are induced in B6.CCR5–/– mice transplanted with complete MHC-mismatched A/J kidneys and are required for rejection of the grafts. This study tested the role of recipient myeloid cell production of myeloperoxidase (MPO) in the cellular and molecular components of acute ABMR. Despite induction of equivalent DSA titers, B6.CCR5–/– recipients rejected A/J kidneys between days 18 and 25, with acute ABMR, whereas B6.CCR5–/–MPO–/– recipients rejected the grafts between days 46 and 54, with histopathological features of chronic graft injury. On day 15, myeloid cells infiltrating grafts from B6.CCR5–/– and B6.CCR5–/–MPO–/– recipients expressed marked phenotypic and functional transcript differences that correlated with the development of acute versus chronic allograft injury, respectively. Near the time of peak DSA titers, activation of NK cells to proliferate and express CD107a was decreased within allografts in B6.CCR5–/–MPO–/– recipients. Despite high titers of DSA, depletion of neutrophils reproduced the inhibition of NK cell activation and decreased macrophage infiltration but increased monocytes producing MPO. Overall, recipient myeloid cells producing MPO regulate graft-infiltrating monocyte/macrophage function and NK cell activation that are required for DSA-mediated acute kidney allograft injury, and their absence switches DSA-mediated acute pathology and graft outcomes to chronic ABMR.

Authors

Satoshi Miyairi, Daisuke Ueda, Takafumi Yagisawa, Daigo Okada, Karen S. Keslar, Kazunari Tanabe, Nina Dvorina, Anna Valujskikh, William M. Baldwin 3rd, Stanley L. Hazen, Robert L. Fairchild

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Epitope-specific antibody responses differentiate COVID-19 outcomes and variants of concern
Courtney Voss, … , Ian Chin-Yee, Shawn S.C. Li
Courtney Voss, … , Ian Chin-Yee, Shawn S.C. Li
Published June 3, 2021
Citation Information: JCI Insight. 2021;6(13):e148855. https://doi.org/10.1172/jci.insight.148855.
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Epitope-specific antibody responses differentiate COVID-19 outcomes and variants of concern

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Abstract

BACKGROUND The role of humoral immunity in COVID-19 is not fully understood, owing, in large part, to the complexity of antibodies produced in response to the SARS-CoV-2 infection. There is a pressing need for serology tests to assess patient-specific antibody response and predict clinical outcome.METHODS Using SARS-CoV-2 proteome and peptide microarrays, we screened 146 COVID-19 patients’ plasma samples to identify antigens and epitopes. This enabled us to develop a master epitope array and an epitope-specific agglutination assay to gauge antibody responses systematically and with high resolution.RESULTS We identified linear epitopes from the spike (S) and nucleocapsid (N) proteins and showed that the epitopes enabled higher resolution antibody profiling than the S or N protein antigen. Specifically, we found that antibody responses to the S-811–825, S-881–895, and N-156–170 epitopes negatively or positively correlated with clinical severity or patient survival. Moreover, we found that the P681H and S235F mutations associated with the coronavirus variant of concern B.1.1.7 altered the specificity of the corresponding epitopes.CONCLUSION Epitope-resolved antibody testing not only affords a high-resolution alternative to conventional immunoassays to delineate the complex humoral immunity to SARS-CoV-2 and differentiate between neutralizing and non-neutralizing antibodies, but it also may potentially be used to predict clinical outcome. The epitope peptides can be readily modified to detect antibodies against variants of concern in both the peptide array and latex agglutination formats.FUNDING Ontario Research Fund (ORF) COVID-19 Rapid Research Fund, Toronto COVID-19 Action Fund, Western University, Lawson Health Research Institute, London Health Sciences Foundation, and Academic Medical Organization of Southwestern Ontario (AMOSO) Innovation Fund.

Authors

Courtney Voss, Sally Esmail, Xuguang Liu, Michael J. Knauer, Suzanne Ackloo, Tomonori Kaneko, Lori Lowes, Peter Stogios, Almagul Seitova, Ashley Hutchinson, Farhad Yusifov, Tatiana Skarina, Elena Evdokimova, Peter Loppnau, Pegah Ghiabi, Taraneh Haijan, Shanshan Zhong, Husam Abdoh, Benjamin D. Hedley, Vipin Bhayana, Claudio M. Martin, Marat Slessarev, Benjamin Chin-Yee, Douglas D. Fraser, Ian Chin-Yee, Shawn S.C. Li

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Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation
Simona Pagliuca, … , Betty K. Hamilton, Jaroslaw P. Maciejewski
Simona Pagliuca, … , Betty K. Hamilton, Jaroslaw P. Maciejewski
Published July 8, 2021
Citation Information: JCI Insight. ;6(13):e149080. https://doi.org/10.1172/jci.insight.149080.
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Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation

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Abstract

TCR repertoire diversification constitutes a foundation for successful immune reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT). Deep TCR Vβ sequencing of 135 serial specimens from a cohort of 35 allo-HCT recipients/donors was performed to dissect posttransplant TCR architecture and dynamics. Paired analysis of clonotypic repertoires showed a minimal overlap with donor expansions. Rarefied and hyperexpanded clonotypic patterns were hallmarks of T cell reconstitution and influenced clinical outcomes. Donor and pretransplant TCR diversity as well as divergence of class I human leukocyte antigen genotypes were major predictors of recipient TCR repertoire recovery. Complementary determining region 3–based specificity spectrum analysis indicated a predominant expansion of pathogen- and tumor-associated clonotypes in the late post–allo-HCT phase, while autoreactive clones were more expanded in the case of graft-versus-host disease occurrence. These findings shed light on post–allo-HCT adaptive immune reconstitution processes and possibly help in tracking alloreactive responses.

Authors

Simona Pagliuca, Carmelo Gurnari, Sanghee Hong, Ran Zhao, Sunisa Kongkiatkamon, Laila Terkawi, Misam Zawit, Yihong Guan, Hassan Awada, Ashwin Kishtagari, Cassandra M. Kerr, Thomas LaFramboise, Bhumika J. Patel, Babal K. Jha, Hetty E. Carraway, Valeria Visconte, Navneet S. Majhail, Betty K. Hamilton, Jaroslaw P. Maciejewski

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Association of immune cell subsets with cardiac mechanics in the Multi-Ethnic Study of Atherosclerosis
Arjun Sinha, … , Russel P. Tracy, Bruce M. Psaty
Arjun Sinha, … , Russel P. Tracy, Bruce M. Psaty
Published July 8, 2021
Citation Information: JCI Insight. 2021;6(13):e149193. https://doi.org/10.1172/jci.insight.149193.
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Association of immune cell subsets with cardiac mechanics in the Multi-Ethnic Study of Atherosclerosis

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Abstract

Background Immunomodulatory therapy may help prevent heart failure (HF). Data on immune cells and myocardial remodeling in older adults with cardiovascular risk factors are limited.Methods In the Multi-Ethnic Study of Atherosclerosis cohort, 869 adults had 19 peripheral immune cell subsets measured and underwent cardiac MRI during the baseline exam, of which 321 had assessment of left ventricular global circumferential strain (LV-GCS). We used linear regression with adjustment for demographics, cardiovascular risk factors, and cytomegalovirus serostatus to evaluate the cross-sectional association of immune cell subsets with left ventricular mass index (LVMI) and LV-GCS.Results The average age of the cohort was 61.6 ± 10.0 years and 53% were women. Higher proportions of γ/δ T cells were associated with lower absolute (worse) LV-GCS (–0.105% [95% CI –0.164%, –0.046%] per 1 SD higher proportion of γ/δ T cells, P = 0.0006). This association remained significant after Bonferroni’s correction. Higher proportions of classical monocytes were associated with worse absolute LV-GCS (–0.04% [95% CI –0.07%, 0.00%] per 1 SD higher proportion of classical monocytes, P = 0.04). This did not meet significance after Bonferroni’s correction. There were no other significant associations with LV-GCS or LVMI.Conclusion Pathways associated with γ/δ T cells may be potential targets for immunomodulatory therapy targeted at HF prevention in populations at risk.Funding Contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 and grant R01 HL98077 from the National Heart, Lung, and Blood Institute/NIH and grants KL2TR001424, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences/NIH.

Authors

Arjun Sinha, Adovich S. Rivera, Margaret F. Doyle, Colleen Sitlani, Alison Fohner, Sally A. Huber, Nels C. Olson, Joao A.C. Lima, Joseph A. Delaney, Matthew J. Feinstein, Sanjiv J. Shah, Russel P. Tracy, Bruce M. Psaty

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Placental mTOR complex 1 regulates fetal programming of obesity and insulin resistance in mice
Brian Akhaphong, … , Maria Ruth B. Pineda-Cortel, Emilyn U. Alejandro
Brian Akhaphong, … , Maria Ruth B. Pineda-Cortel, Emilyn U. Alejandro
Published May 25, 2021
Citation Information: JCI Insight. 2021;6(13):e149271. https://doi.org/10.1172/jci.insight.149271.
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Placental mTOR complex 1 regulates fetal programming of obesity and insulin resistance in mice

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Fetal growth restriction, or low birth weight, is a strong determinant for eventual obesity and type 2 diabetes. Clinical studies suggest placental mechanistic target of rapamycin (mTOR) signaling regulates fetal birth weight and the metabolic health trajectory of the offspring. In the current study, we used a genetic model with loss of placental mTOR function (mTOR-KOPlacenta) to test the direct role of mTOR signaling on birth weight and metabolic health in the adult offspring. mTOR-KOPlacenta animals displayed reduced placental area and total weight, as well as fetal body weight at embryonic day (E) 17.5. Birth weight and serum insulin levels were reduced; however, β cell mass was normal in mTOR-KOPlacenta newborns. Adult mTOR-KOPlacenta offspring, under a metabolic high-fat challenge, displayed exacerbated obesity and metabolic dysfunction compared with littermate controls. Subsequently, we tested whether enhancing placental mTOR complex 1 (mTORC1) signaling, via genetic ablation of TSC2, in utero would improve glucose homeostasis in the offspring. Indeed, increased placental mTORC1 conferred protection from diet-induced obesity in the offspring. In conclusion, placental mTORC1 serves as a mechanistic link between placental function and programming of obesity and insulin resistance in the adult offspring.

Authors

Brian Akhaphong, Daniel C. Baumann, Megan Beetch, Amber D. Lockridge, Seokwon Jo, Alicia Wong, Tate Zemanovic, Ramkumar Mohan, Danica L. Fondevilla, Michelle Sia, Maria Ruth B. Pineda-Cortel, Emilyn U. Alejandro

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GADD45A is a protective modifier of neurogenic skeletal muscle atrophy
Jeffrey T. Ehmsen, … , Giovanni Coppola, Ahmet Höke
Jeffrey T. Ehmsen, … , Giovanni Coppola, Ahmet Höke
Published June 15, 2021
Citation Information: JCI Insight. 2021;6(13):e149381. https://doi.org/10.1172/jci.insight.149381.
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GADD45A is a protective modifier of neurogenic skeletal muscle atrophy

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Abstract

Neurogenic muscle atrophy is the loss of skeletal muscle mass and function that occurs with nerve injury and in denervating diseases, such as amyotrophic lateral sclerosis. Aside from prompt restoration of innervation and exercise where feasible, there are currently no effective strategies for maintaining skeletal muscle mass in the setting of denervation. We conducted a longitudinal analysis of gene expression changes occurring in atrophying skeletal muscle and identified growth arrest and DNA damage-inducible A (Gadd45a) as a gene that shows one of the earliest and most sustained increases in expression in skeletal muscle after denervation. We evaluated the role of this induction using genetic mouse models and found that mice lacking GADD45A showed accelerated and exacerbated neurogenic muscle atrophy, as well as loss of fiber type identity. Our genetic analyses demonstrate that, rather than directly contributing to muscle atrophy as proposed in earlier studies, GADD45A induction likely represents a protective negative feedback response to denervation. Establishing the downstream effectors that mediate this protective effect and the pathways they participate in may yield new opportunities to modify the course of muscle atrophy.

Authors

Jeffrey T. Ehmsen, Riki Kawaguchi, Damlanur Kaval, Anna E. Johnson, Daniel Nachun, Giovanni Coppola, Ahmet Höke

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Combining multiomics and drug perturbation profiles to identify muscle-specific treatments for spinal muscular atrophy
Katharina E. Meijboom, … , Caleb Webber, Melissa Bowerman
Katharina E. Meijboom, … , Caleb Webber, Melissa Bowerman
Published July 8, 2021
Citation Information: JCI Insight. 2021;6(13):e149446. https://doi.org/10.1172/jci.insight.149446.
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Combining multiomics and drug perturbation profiles to identify muscle-specific treatments for spinal muscular atrophy

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Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of survival motor neuron (SMN) protein. While SMN restoration therapies are beneficial, they are not a cure. We aimed to identify potentially novel treatments to alleviate muscle pathology combining transcriptomics, proteomics, and perturbational data sets. This revealed potential drug candidates for repurposing in SMA. One of the candidates, harmine, was further investigated in cell and animal models, improving multiple disease phenotypes, including lifespan, weight, and key molecular networks in skeletal muscle. Our work highlights the potential of multiple and parallel data-driven approaches for the development of potentially novel treatments for use in combination with SMN restoration therapies.

Authors

Katharina E. Meijboom, Viola Volpato, Jimena Monzón-Sandoval, Joseph M. Hoolachan, Suzan M. Hammond, Frank Abendroth, Olivier G. de Jong, Gareth Hazell, Nina Ahlskog, Matthew J.A. Wood, Caleb Webber, Melissa Bowerman

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Inflammatory signals are sufficient to elicit TOX expression in mouse and human CD8+ T cells
Nicholas J. Maurice, … , Dietmar Zehn, Martin Prlic
Nicholas J. Maurice, … , Dietmar Zehn, Martin Prlic
Published May 25, 2021
Citation Information: JCI Insight. 2021;6(13):e150744. https://doi.org/10.1172/jci.insight.150744.
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Inflammatory signals are sufficient to elicit TOX expression in mouse and human CD8+ T cells

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Abstract

T cell receptor (TCR) stimulation leads to the expression of the transcription factor thymocyte selection–associated high-mobility group box (TOX). Prolonged TCR signaling, such as encountered during chronic infections or in tumors, leads to sustained TOX expression, which is required for the induction of a state of exhaustion or dysfunction. Although CD8+ memory T (Tmem) cells in mice typically do not express TOX at steady state, some human Tmem cells express TOX but appear fully functional. This seeming discrepancy between mouse and human T cells has led to the speculation that TOX is differentially regulated between these species, which could complicate the interpretation of preclinical mouse model studies. We report here that, similar to TCR-mediated signals, inflammatory cytokines are also sufficient to increase TOX expression in human and mouse Tmem cells. Thus, TOX expression is controlled by the environment, which provides an explanation for the different TOX expression patterns encountered in T cells isolated from specific pathogen–free laboratory mice versus humans. Finally, we report that TOX is not necessary for cytokine-driven expression of programmed cell death 1. Overall, our data highlight that the mechanisms regulating TOX expression are conserved across species and indicate that TOX expression reflects a T cell’s activation state and does not necessarily correlate with T cell dysfunction.

Authors

Nicholas J. Maurice, Jacqueline Berner, Alexis K. Taber, Dietmar Zehn, Martin Prlic

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