Inflammation following mesh implantation
In this issue of JCI Insight, Heymann et al. demonstrate that polypropylene mesh implantation in mice induces rapid myeloid cell accumulation and causes persistent inflammation. The cover image shows immunofluorescence microscopy of IgM (green) deposition and macrophage infiltration (red) surrounding mesh fibers.
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Review
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Abstract
Sepsis-induced acute respiratory distress syndrome (ARDS) has high morbidity and mortality and arises after lung infection or infection at extrapulmonary sites. An aberrant host response to infection leads to disruption of the pulmonary alveolar-capillary barrier, resulting in lung injury characterized by hypoxemia, inflammation, and noncardiogenic pulmonary edema. Despite increased understanding of the molecular biology underlying sepsis-induced ARDS, there are no targeted pharmacologic therapies for this devastating condition. Here, we review the molecular underpinnings of sepsis-induced ARDS with a focus on relevant clinical and translational studies that point toward novel therapeutic strategies.
Authors
Joshua A. Englert, Christopher Bobba, Rebecca M. Baron
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Research Articles
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Abstract
Liver cancer is the fourth leading cause of cancer-related mortality and is distinguished by a relative paucity of chemotherapy options. It has been hypothesized that intratumor genetic heterogeneity may contribute to the high failure rate of chemotherapy. Here, we evaluated functional heterogeneity in a cohort of primary human liver cancer organoid lines. Each primary human liver cancer surgical specimen was used to generate multiple cancer organoid lines, obtained from distinct regions of the tumor. A total of 27 liver cancer lines were established and tested with 129 cancer drugs, generating 3,483 cell survival data points. We found a rich intratumor, functional (drug response) heterogeneity in our liver cancer patients. Furthermore, we established that the majority of drugs were either ineffective, or effective only in select organoid lines. In contrast, we found that a subset of drugs appeared pan-effective, displaying at least moderate activity in the majority of these cancer organoid lines. These drugs, which are FDA approved for indications other than liver cancers, deserve further consideration as either systemic or local therapeutics. Of note, molecular profiles, obtained for a reduced sample set, did not correlate with the drug response heterogeneity of liver cancer organoid lines. Taken together, these findings lay the foundation for in-depth studies of pan-effective drugs, as well as for functional personalized oncology approaches. Lastly, these functional studies demonstrate the utility of cancer organoid drug testing as part of a drug discovery pipeline.
Authors
Ling Li, Hildur Knutsdottir, Ken Hui, Matthew J. Weiss, Jin He, Benjamin Philosophe, Andrew M. Cameron, Christopher L. Wolfgang, Timothy M. Pawlik, Gabriel Ghiaur, Andrew J. Ewald, Esteban Mezey, Joel S. Bader, Florin M. Selaru
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The antiinflammatory effects of i.v. Ig (IVIG) in the treatment of autoimmune disease are due, in part, to the Fc fragments of Ig aggregates. In order to capitalize on the known antiinflammatory and tolerogenic properties of Ig Fc aggregates, we created a recombinant human IgG1 Fc multimer, GL-2045. In vitro, GL-2045 demonstrated high-avidity binding to Fc receptors, blocked the binding of circulating immune complexes from patients with rheumatoid arthritis to human Fcγ receptors (FcγRs), and inhibited antibody-mediated phagocytosis at log order–lower concentrations than IVIG. In vivo, administration of GL-2045 conferred partial protection against antibody-mediated platelet loss in a murine immune thrombocytopenic purpura (ITP) model. GL-2045 also suppressed disease activity in a therapeutic model of murine collagen-induced arthritis (CIA), which was associated with reduced circulating levels of IL-6. Furthermore, GL-2045 administration to nonhuman primates (NHPs) transiently increased systemic levels of the antiinflammatory cytokines IL-10 and IL-1RA, reduced the proinflammatory cytokine IL-8, and decreased surface expression of CD14 and HLA-DR on monocytes. These findings demonstrate the immunomodulatory properties of GL-2045 and suggest that it has potential as a treatment for autoimmune and inflammatory diseases, as a recombinant alternative to IVIG.
Authors
Xiaoyu Zhang, Jane Owens, Henrik S. Olsen, Edward So, Erin Burch, Mark C. McCroskey, Xianfeng Li, Gregory L. Weber, Donald Bennett, Denis Rybin, Hua Zhou, Haiping Hao, Emmanuel Y. Mérigeon, David S. Block, Gregory LaRosa, Scott E. Strome
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Although the importance of the tumor immune environment for the modulation of tumorigenesis and tumor regression is becoming increasingly clear, most of the research related to tumor-immune therapies has focused on adaptive immune cells, while the role and regulation of innate leukocytes such as neutrophils remains controversial and less defined. Here we observed that the selective deletion of Tollip, a key innate immune-cell modulator, led to enhanced tumor immune surveillance in a chemically induced colorectal cancer model. Tollip-deficient neutrophils significantly elevated T cell activation through enhanced expression of the costimulatory molecule CD80, and reduced expression of the inhibitory molecule PD-L1. Mechanistically, Tollip deficiency increased STAT5 and reduced STAT1, the transcription factors responsible for the expression of CD80 and PD-L1, respectively. Through adoptive transfer, we demonstrate that Tollip-deficient neutrophils, but not Tollip-deficient monocytes, are sufficient to drive enhanced tumor immune surveillance and reduced colorectal cancer burden in vivo. Our data reveal a strategy for the reprogramming of neutrophil functions conducive for the enhancement of the antitumor immune environment.
Authors
Yao Zhang, Christina Lee, Shuo Geng, Liwu Li
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Foxp3+ CD4 Tregs are central regulators of inflammation, including allergic inflammation in the lung. There is increasing evidence that inflammatory factors undermine adequate Treg functions and homeostasis, resulting in prolonged and exacerbated inflammation. Therefore, identifying the factors is of the utmost important. IL-27 is an antiinflammatory cytokine implicated in immune regulation and tolerance. However, the cellular mechanisms underlying IL-27–mediated immune regulation in vivo remain largely unknown. Utilizing a cockroach antigen–induced allergic inflammation model in mice, we sought to test the roles of Tregs during IL-27–mediated regulation of allergic inflammation. Intranasally delivered IL-27 significantly reduced the development of airway inflammation. Unexpectedly, the IL-27–induced reduction occurred only in the presence of Tregs. Il27ra–/– and Treg-specific Il27ra–/– mice developed severe airway inflammation, and IL-27 treatment had little impact on diminishing the inflammatory responses. IL-27–induced treatment was restored following transfer of WT Tregs but not of Tregs deficient in Lag3, a molecule induced by IL-27 in Tregs. Finally, Tregs from asthmatic patients exhibited blunted STAT1 phosphorylation following IL-27 stimulation. Taken together, our results uncover that Tregs are the primary target cells of IL-27 in vivo to mediate its antiinflammatory functions, suggesting that altered IL-27 responsiveness in Tregs may underlie inadequate Treg functions and perpetuation of inflammation.
Authors
Quang Tam Nguyen, Eunjung Jang, Hongnga T. Le, Sohee Kim, Dongkyun Kim, Nina Dvorina, Mark A. Aronica, William M. Baldwin III, Kewal Asosingh, Suzy Comhair, Booki Min
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Psoriasis is one of the most common skin inflammatory diseases worldwide. The vitamin D3 analog calcipotriol has been used alone or in combination with corticosteroids in treating plaque psoriasis, but how it suppresses psoriatic inflammation has not been fully understood. Using an experimental mouse psoriasis model, we show that topical calcipotriol inhibited the pivotal IL-23/IL-17 axis and neutrophil infiltration in psoriatic skin, and interestingly, such effects were mediated through the vitamin D receptor (VDR) in keratinocytes (KCs). We further reveal that IL-36α and IL-36γ, which have recently emerged as key players in psoriasis pathogenesis, were effectively repressed by calcipotriol via direct VDR signaling in mouse KCs. Accordingly, calcipotriol treatment suppressed IL-36α/γ expression in lesional skin from patients with plaque psoriasis, which was accompanied by a reduced IL-23/IL-17 expression. In contrast, dexamethasone indirectly reduced IL-36α/γ expression in mouse psoriatic skin through immune cells. Furthermore, we demonstrate that calcipotriol and dexamethasone, in combination, synergistically suppressed the expression of IL-36α/γ, IL-23, and IL-17 in the established mouse psoriasis. Our findings indicate that the combination of calcipotriol and corticosteroid efficiently disrupts the IL-36 and IL-23/IL-17 positive feedback loop, thus revealing a mechanism underlying the superior efficacy of calcipotriol and corticosteroid combination therapy for psoriasis.
Authors
Beatriz Germán, Ruicheng Wei, Pierre Hener, Christina Martins, Tao Ye, Cornelia Gottwick, Jianying Yang, Julien Seneschal, Katia Boniface, Mei Li
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Tumor radioresistance leading to local therapy failure remains a major obstacle for successful treatment of high-grade glioma. We hypothesized that distinct radiobiological features of particle therapy with carbon ions may circumvent glioma radioresistance. We demonstrate that carbon irradiation (CIR) efficiently eradicates radioresistant patient-derived glioma stem cells (GSCs), leading to growth inhibition and prolonged survival. The impact of CIR at the tumor–stroma interface was further investigated in 2 syngeneic mouse and 2 orthotopic GSC xenograft models. Intriguingly, tumor regressions and long-term local controls were observed at doses greater than or equal to 15-Gy CIR. Fractionated CIR further prolonged survival. The enhanced relative biological effectiveness of CIR in vivo was attributed to its potent antiangiogenic effects and eradication of radioresistant hypoxic tumor cells. Blockade of the HIF1-α/stromal cell–derived factor 1/CXCR4 axis by CIR reduced the recruitment of microglia and myeloid-derived suppressor cells (CD11b+Gr1+). Consequently, CIR abrogated M2-like immune polarization and enhanced the influx of CD8+ cells, generating an immunopermissive niche. We report that radiotherapy with carbon ions could surmount several central glioma resistance mechanisms by eradicating hypoxic and stem cell–like tumor cells, as well as modulating the glioma niche toward an antiangiogenic and less immunosuppressive state. Conclusively, potentially novel rationales for CIR in conquering glioma radioresistance are provided.
Authors
Sara Chiblak, Zili Tang, Dieter Lemke, Maximilian Knoll, Ivana Dokic, Rolf Warta, Mahmoud Moustafa, Walter Mier, Stephan Brons, Carmen Rapp, Stefan Muschal, Philipp Seidel, Martin Bendszus, Sebastian Adeberg, Otmar D. Wiestler, Uwe Haberkorn, Jürgen Debus, Christel Herold-Mende, Wolfgang Wick, Amir Abdollahi
×Polypropylene mesh implantation for hernia repair causes myeloid cell–driven persistent inflammation
Abstract
Polypropylene meshes that are commonly used for inguinal hernia repair may trigger granulomatous foreign body reactions. Here, we show that asymptomatic patients display mesh-associated inflammatory granulomas long after surgery, which are dominated by monocyte-derived macrophages expressing high levels of inflammatory activation markers. In mice, mesh implantation by the onlay technique induced rapid and strong myeloid cell accumulation, without substantial attenuation for up to 90 days. Myeloid cells segregated into distinct macrophage subsets with separate spatial distribution, activation profiles, and functional properties, showing a stable inflammatory phenotype in the tissue surrounding the biomaterial and a mixed, wound-healing phenotype in the surrounding stromal tissue. Protein mass spectrometry confirmed the inflammatory nature of the foreign body reaction, as characterized by cytokines, complement activation, and matrix-modulating factors. Moreover, immunoglobulin deposition increased over time around the implant, arguing for humoral immune responses in association with the cell-driven inflammation. Intravital multiphoton microscopy revealed a high motility and continuous recruitment of myeloid cells, which is partly dependent on the chemokine receptor CCR2. CCR2-dependent macrophages are particular drivers of fibroblast proliferation. Thus, our work functionally characterizes myeloid cell–dependent inflammation following mesh implantation, thereby providing insights into the dynamics and mechanisms of foreign body reactions to implanted biomaterials.
Authors
Felix Heymann, Klaus-Thilo von Trotha, Christian Preisinger, Petra Lynen-Jansen, Anjali A. Roeth, Melanie Geiger, Lukas Jonathan Geisler, Anna Katharina Frank, Joachim Conze, Tom Luedde, Christian Trautwein, Marcel Binnebösel, Ulf P. Neumann, Frank Tacke
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Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are chronic inflammatory demyelinating and neurodegenerative diseases of the CNS. Although neurodegeneration is the major contributor to chronic disability in MS, mechanisms governing the viability of axons and neurons in MS and EAE remain elusive. Data indicate that activation of pancreatic endoplasmic reticulum kinase (PERK) influences, positively or negatively, neuron and axon viability in various neurodegenerative diseases through induction of ATF4. In this study, we demonstrate that the PERK pathway was activated in neurons during EAE. We found that neuron-specific PERK inactivation impaired EAE resolution and exacerbated EAE-induced axon degeneration, neuron loss, and demyelination. Surprisingly, neuron-specific ATF4 inactivation did not alter EAE disease course or EAE-induced axon degeneration, neuron loss, and demyelination. These results suggest that PERK activation in neurons protects axons and neurons against inflammation in MS and EAE through ATF4-independent mechanisms.
Authors
Sarrabeth Stone, Yuan Yue, Milos Stanojlovic, Shuangchan Wu, Gerard Karsenty, Wensheng Lin
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BACKGROUND. Oculocutaneous albinism (OCA) results in reduced melanin synthesis, skin hypopigmentation, increased risk of UV-induced malignancy, and developmental eye abnormalities affecting vision. No treatments exist. We have shown that oral nitisinone increases ocular and fur pigmentation in a mouse model of one form of albinism, OCA-1B, due to hypomorphic mutations in the Tyrosinase gene. METHODS. In this open-label pilot study, 5 adult patients with OCA-1B established baseline measurements of iris, skin, and hair pigmentation and were treated over 12 months with 2 mg/d oral nitisinone. Changes in pigmentation and visual function were evaluated at 3-month intervals. RESULTS. The mean change in iris transillumination, a marker of melanin, from baseline was 1.0 ± 1.54 points, representing no change. The method of iris transillumination grading showed a high intergrader reliability (intraclass correlation coefficient ≥ 0.88 at each visit). The number of letters read (visual acuity) improved significantly at month 12 for both eyes (right eye, OD, mean 4.2 [95% CI, 0.3, 8.1], P = 0.04) and left eye (OS, 5 [1.0, 9.1], P = 0.003). Skin pigmentation on the inner bicep increased (M index increase = 1.72 [0.03, 3.41], P = 0.047). Finally, hair pigmentation increased by both reflectometry (M index [17.3 {4.4, 30.2}, P = 0.01]) and biochemically. CONCLUSION. Nitisinone did not result in an increase in iris melanin content but may increase hair and skin pigmentation in patients with OCA-1B. The iris transillumination grading scale used in this study proved robust, with potential for use in future clinical trials. TRIAL REGISTRATION. ClinicalTrials.gov NCT01838655. FUNDING. Intramural program of the National Eye Institute.
Authors
David R. Adams, Supriya Menezes, Ramon Jauregui, Zaheer M. Valivullah, Bradley Power, Maria Abraham, Brett G. Jeffrey, Angel Garced, Ramakrishna P. Alur, Denise Cunningham, Edythe Wiggs, Melissa A. Merideth, Pei-Wen Chiang, Shanna Bernstein, Shosuke Ito, Kazumasa Wakamatsu, Rhona M. Jack, Wendy J. Introne, William A. Gahl, Brian P. Brooks
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Systemic lupus erythematosus (SLE) is a highly variable autoimmune disease that can involve severe organ-threatening symptoms, such as lupus nephritis. Certain drugs, such as mycophenolate mofetil (MMF), are effective at reducing morbidity associated with nephritis; however, the immune pathways associated with disease suppression are poorly defined. Here, we provide evidence that MMF inhibits phosphorylation of STAT3 and other associated immune pathways. Using mass cytometry and bead-based or ELISA assays, the systemic phenotype of SLE patients not taking (MMF–) or taking (MMF+) MMF were studied. MMF+ SLE patients had significant reductions in total numbers of transitional B cells, plasmablasts, and T cells, specifically CD4+ Th17-type and CD4+ Treg-type cells, compared with MMF– patients. Plasma soluble mediators were decreased in MMF+ patients including chemokines (MIG/CXCL9 and SDF-1α/CXCL12) and growth factors (VEGF-A and PDGF-BB). Soluble mediators and cell subsets grouped by functional properties revealed significant modifications associated with STAT3 and B cell pathways. Further, healthy PBMCs treated with IL-6 revealed a reduction in p-STAT3 following the addition of mycophenolic acid (the active metabolite of MMF). In conclusion, the inhibition of STAT3 phosphorylation by MMF may explain the effectiveness of this treatment in SLE patients, since increased levels of p-STAT3 are associated with disease pathology.
Authors
Samantha Slight-Webb, Joel M. Guthridge, Eliza F. Chakravarty, Hua Chen, Rufei Lu, Susan Macwana, Krista Bean, Holden T. Maecker, Paul J. Utz, Judith A. James
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Patients with heterozygous missense mutations in the ACTA2 or MYH11 gene are known to exhibit thoracic aortic aneurysm and a risk of early-onset aortic dissection. However, less common phenotypes involving arterial obstruction are also observed, including coronary and cerebrovascular stenotic disease. Herein we implicate the HDAC9 complex in transcriptional silencing of contractile protein–associated genes, known to undergo downregulation in stenotic lesions. Furthermore, neointimal formation was inhibited in HDAC9- or MALAT1-deficient mice with preservation of contractile protein expression. Pharmacologic targeting of the HDAC9 complex through either MALAT1 antisense oligonucleotides or inhibition of the methyltransferase EZH2 (catalytic mediator recruited by the HDAC9 complex) reduced neointimal formation. In conclusion, we report the implication of the HDAC9 complex in stenotic disease and demonstrate that pharmacologic therapy targeting epigenetic complexes can ameliorate arterial obstruction in an experimental system.
Authors
Christian L. Lino Cardenas, Chase W. Kessinger, Elizabeth Chou, Brian Ghoshhajra, Ashish S. Yeri, Saumya Das, Neal L. Weintraub, Rajeev Malhotra, Farouc A. Jaffer, Mark E. Lindsay
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Primary prostate cancer lesions are clonally heterogeneous and often arise independently. In contrast, metastases were reported to share a monoclonal background. Because prostate cancer mortality is the consequence of distant metastases, prevention of metastatic outgrowth by primary tumor ablation is the main focus of treatment for localized disease. Focal therapy is targeted ablation of the primary index lesion, but it is unclear whether remaining primary lesions metastasize at a later stage. In this study, we compared copy number aberration profiles of primary prostate cancer lesions with matching pelvic lymph node metastases of 30 patients to establish clonality between a lymph node metastasis and multiple primary lesions within the same patient. Interestingly, in 23.3% of the cases, the regional metastasis was not clonally linked to the index primary lesion. These findings suggest that focal ablation of only the index lesion is potentially an undertreatment of a significant proportion of prostate cancer patients.
Authors
Jeroen Kneppers, Oscar Krijgsman, Monique Melis, Jeroen de Jong, Daniel S. Peeper, Elise Bekers, Henk G. van der Poel, Wilbert Zwart, Andries M. Bergman
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Here, we report a pathogenic role for type I IFN (IFN-I) signaling in macrophages, and not β cells in the islets, for the development of type 1 diabetes (T1D). Following lymphocytic choriomeningitis (LCMV) infection in the Rip-LCMV-GP T1D model, macrophages accumulated near islets and in close contact to islet-infiltrating GP-specific (autoimmune) CD8+ T cells. Depletion of macrophages with clodronate liposomes or genetic ablation of Ifnar in macrophages aborted T1D, despite proliferation of GP-specific (autoimmune) CD8+ T cells. Histopathologically, disrupted IFNα/β receptor (IFNAR) signaling in macrophages resulted in restriction of CD8+ T cells entering into the islets with significant lymphoid accumulation around the islet. Collectively, these results provide evidence that macrophages via IFN-I signaling, while not entering the islets, are directly involved in interacting, directing, or restricting trafficking of autoreactive-specific T cells into the islets as an important component in causing T1D.
Authors
Brett S. Marro, Sarah Legrain, Brian C. Ware, Michael B.A. Oldstone
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Osteoarthritis (OA) is a leading cause of disability, globally. Despite an emerging role for synovial inflammation in OA pathogenesis, attempts to target inflammation therapeutically have had limited success. A better understanding of the cellular and molecular processes occurring in the OA synovium is needed to develop novel therapeutics. We investigated macrophage phenotype and gene expression in synovial tissue of OA and inflammatory-arthritis (IA) patients. Compared with IA, OA synovial tissue contained higher but variable proportions of macrophages (P < 0.001). These macrophages exhibited an activated phenotype, expressing folate receptor-2 and CD86, and displayed high phagocytic capacity. RNA sequencing of synovial macrophages revealed 2 OA subgroups. Inflammatory-like OA (iOA) macrophages are closely aligned to IA macrophages and are characterized by a cell proliferation signature. In contrast, classical OA (cOA) macrophages display cartilage remodeling features. Supporting these findings, when compared with cOA, iOA synovial tissue contained higher proportions of macrophages (P < 0.01), expressing higher levels of the proliferation marker Ki67 (P < 0.01). These data provide new insight into the heterogeneity of OA synovial tissue and suggest distinct roles of macrophages in pathogenesis. Our findings could lead to the stratification of OA patients for suitable disease-modifying treatments and the identification of novel therapeutic targets.
Authors
Matthew J. Wood, Adam Leckenby, Gary Reynolds, Rachel Spiering, Arthur G. Pratt, Kenneth S. Rankin, John D. Isaacs, Muzlifah A. Haniffa, Simon Milling, Catharien M.U. Hilkens
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Acute kidney injury (AKI) is a common clinical condition of growing incidence. Patients who suffer severe AKI have a higher risk of developing interstitial fibrosis, chronic kidney disease, and end-stage renal disease later in life. Cellular senescence is a persistent cell cycle arrest and altered gene expression pattern evoked by multiple stressors. The number of senescent cells increases with age and even in small numbers these cells can induce chronic inflammation and fibrosis; indeed, in multiple organs including kidneys, the accumulation of such cells is a hallmark of aging. We hypothesized that cellular senescence might be induced in the kidney after injury and that this might contribute to progressive organ fibrosis. Testing this hypothesis, we found that tubular epithelial cells (TECs) in mice senesce within a few days of kidney injury and that this response is mediated by epithelial Toll-like and interleukin 1 receptors (TLR/IL-1R) of the innate immune system. Epithelial cell–specific inhibition of innate immune signaling in mice by knockout of myeloid differentiation 88 (Myd88) reduced fibrosis as well as damage to kidney tubules, and also prevented the accumulation of senescent TECs. Importantly, although inactivation of Myd88 after injury ameliorated fibrosis, it did not reduce damage to the tubules. Selectively induced apoptosis of senescent cells by two different approaches only partially reduced kidney fibrosis, without ameliorating damage to the tubules. Our data reveal a cell-autonomous role for epithelial innate immunity in controlling TEC senescence after kidney injury, and additionally suggest that early therapeutic intervention is required for effective reduction of long-term sequelae of AKI.
Authors
Heng Jin, Yan Zhang, Qiong Ding, Shan Shan Wang, Prerna Rastogi, Dao-Fu Dai, Dongmei Lu, Madison Purvis, Chao Cao, Angela Wang, Dingxiao Liu, Chongyu Ren, Sarah Elhadi, Ming-Chang Hu, Yanfen Chai, Diana Zepeda-Orozco, Judith Campisi, Massimo Attanasio
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Acute kidney injury (AKI) is a devastating clinical condition affecting at least two-thirds of critically ill patients, and, among these patients, it is associated with a greater than 60% risk of mortality. Kidney mononuclear phagocytes (MPs) are implicated in pathogenesis and healing in mouse models of AKI and, thus, have been the subject of investigation as potential targets for clinical intervention. We have determined that, after injury, F4/80hi-expressing kidney-resident macrophages (KRMs) are a distinct cellular subpopulation that does not differentiate from nonresident infiltrating MPs. However, if KRMs are depleted using polyinosinic/polycytidylic acid (poly I:C), they can be reconstituted from bone marrow–derived precursors. Further, KRMs lack major histocompatibility complex class II (MHCII) expression before P7 but upregulate it over the next 14 days. This MHCII– KRM phenotype reappears after injury. RNA sequencing shows that injury causes transcriptional reprogramming of KRMs such that they more closely resemble that found at P7. KRMs after injury are also enriched in Wingless-type MMTV integration site family (Wnt) signaling, indicating that a pathway vital for mouse and human kidney development is active. These data indicate that mechanisms involved in kidney development may be functioning after injury in KRMs.
Authors
Jeremie M. Lever, Travis D. Hull, Ravindra Boddu, Mark E. Pepin, Laurence M. Black, Oreoluwa O. Adedoyin, Zhengqin Yang, Amie M. Traylor, Yanlin Jiang, Zhang Li, Jacelyn E. Peabody, Han E. Eckenrode, David K. Crossman, Michael R. Crowley, Subhashini Bolisetty, Kurt A. Zimmerman, Adam R. Wende, Michal Mrug, Bradley K. Yoder, Anupam Agarwal, James F. George
×Abstract
BACKGROUND. Human cytomegalovirus (CMV) reactivation is a common occurrence early after transplant and is associated with heterogeneous NK cell subset expansion. These adaptive NK cell expansions are highly variable between recipients, with respect to magnitude and relative frequencies of adaptive NK cell subsets. METHODS. To gain insight into the factors that influence adaptive NK cell expansion from a CMV naive graft source, we performed a high-resolution NK cell and CD8+ T cell phenotypic analysis of 215 patients with hematological malignancies that were transplanted with 2 partially HLA matched CMV negative umbilical cord blood units. RESULTS. We found that adaptive NK cells were significantly higher in recipients who received nonmyeloablative conditioning (NMAC) relative to myeloablative conditioning (MAC), and high CMV neutralizing antibody titers correlated with the degree of adaptive NK cell expansion. The frequencies of adaptive NK cell subsets (defined by NKG2C, FcεRγ, EAT-2, and SYK expression) that reconstitute from donor hematopoietic progenitor cells largely matched the frequencies observed in the NK cell compartment of the recipient prior to conditioning, suggesting that host — as well as viral reactivation factors — may determine the phenotypic diversification after transplant. Additionally, multivariable analyses show that higher adaptive NK cell expansion associated with better disease-free survival. CONCLUSIONS. Our findings provide important insights into adaptive NK cell reconstitution after transplant and support a role for adaptive NK cells in promoting better clinical outcomes. FUNDING. The NIH and the National Marrow Donor Program.
Authors
Frank Cichocki, Emily Taras, Flavia Chiuppesi, John E. Wagner, Bruce R. Blazar, Claudio Brunstein, Xianghua Luo, Don J. Diamond, Sarah Cooley, Daniel J. Weisdorf, Jeffrey S. Miller
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Among other cells, macrophages regulate the inflammatory and reparative phases during wound healing but genetic determinants and detailed molecular pathways that modulate these processes are not fully elucidated. Here, we took advantage of normal variation in wound healing in 1,378 genetically outbred mice, and carried out macrophage RNA-sequencing profiling of mice with extreme wound healing phenotypes (i.e., slow and fast healers, n = 146 in total). The resulting macrophage coexpression networks were genetically mapped and led to the identification of a unique module under strong trans-acting genetic control by the Runx2 locus. This macrophage-mediated healing network was specifically enriched for cholesterol and fatty acid biosynthetic processes. Pharmacological blockage of fatty acid synthesis with cerulenin resulted in delayed wound healing in vivo, and increased macrophage infiltration in the wounded skin, suggesting the persistence of an unresolved inflammation. We show how naturally occurring sequence variation controls transcriptional networks in macrophages, which in turn regulate specific metabolic pathways that could be targeted in wound healing.
Authors
Marta Bagnati, Aida Moreno-Moral, Jeong-Hun Ko, Jérôme Nicod, Nathan Harmston, Martha Imprialou, Laurence Game, Jesus Gil, Enrico Petretto, Jacques Behmoaras
