BAFF promotes follicular helper T cell development and germinal center formation through BR3 signal

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Abstract

T follicular helper (Tfh) cells represent an important subset of CD4+ T cells that is crucial to the maturation and differentiation of B cells and the production of high-affinity antibodies. Since BAFF, a vital B cell survival factor, is also crucial to B cell maturation and differentiation, we assessed the effects of BAFF on Tfh cell development and function. We demonstrate that deficiency of BAFF, but not of APRIL, markedly inhibits Tfh cell development, germinal center (GC) formation, and antigen-specific antibody production. The promoting effect of BAFF on Tfh cell development is dependent on expression of BR3 on T cells, and its promoting effect on GC formation is dependent on expression of BR3 on both T cells and B cells. BAFF directly promotes expression of the Tfh cell-characteristic genes via NF-κB signaling. This effect does need BR3 expression. Thus, BAFF not only has direct effects on B cells, but it also has direct effects on Tfh cell differentiation via engagement of BR3 which collectively promote GC formation and production of high-affinity antibodies. This dual effect of BAFF on B cells and Tfh cells may help explain the clinical utility of BAFF antagonists in the management of certain autoimmune diseases.

Authors

Ye Chen, Maogen Chen, Yu Liu, Qiang Li, Youqiu Xue, Liu Liu, Rongzhen Liang, Yiding Xiong, Jun Zhao, Jingrong Chen, Weidong Lin, Julie Wang, YunFeng Pan, William Stohl, Song Guo Zheng

A positive cytokine/chemokine feedback loop establishes plasmacytoid dendritic cell-driven autoimmune pancreatitis in IgG4-related disease

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Abstract

The pathogenesis of the murine model of autoimmune pancreatitis associated with IgG4-related disease (AIP/IgG4-RD) induced by administration of polyinosinic-polycytidylic acid, is incompletely understood. While it is known that murine and human AIP/IgG4-RD is driven by plasmacytoid dendritic cells (pDCs) producing IFN-α, the origin of these cells and their relation to effector T cells is not known. Here we show that murine AIP was initiated by TLR3-bearing conventional DCs in the uninflamed pancreas whose activation by TLR3 ligand (polyinosinic-polycytidylic acid) caused IFN-α, CXCL9, and CXCL10 secretion. This, in turn, induced pancreatic recruitment of CXCR3+ T cells and these T cells, via their secretion of CCL25, facilitated migration of pDCs bearing CCR9 into the pancreas. This established a feedback loop anchored by the now dominant pDC production of IFN-α and the continued CXCR3+ T cell facilitation of pDC migration. Remarkably, the interaction between CXCR3+ T cells and pDCs also existed at the functional levels since this interaction enhanced the production of CCL25 and IFN-α by CXCR3+ T cells and pDCs, respectively. Evidence presented here that a similar disease mechanism was present in human AIP/IgG4-RD creates new avenues of disease treatment.

Authors

Akane Hara, Tomohiro Watanabe, Kosuke Minaga, Tomoe Yoshikawa, Masayuki Kurimoto, Ikue Sekai, Yasuhiro Masuta, Ryutaro Takada, Yasuo Otsuka, Ken Kamata, Shiki Takamura, Masatoshi Kudo, Warren Strober

Dopamine receptor autoantibody signaling in infectious sequelae differentiates movement versus neuropsychiatric disorders

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Abstract

Despite growing recognition, neuropsychiatric diseases associated with infections are a major unsolved problem worldwide. Group A streptococcal (GAS) infections can cause autoimmune sequelae characterized by movement disorders, such as Sydenham chorea (SC), and neuropsychiatric disorders. The molecular mechanisms underlying these diseases are not fully understood. Our previous work demonstrates that autoantibodies (AAbs) can target dopaminergic neurons and increase dopamine receptor D2 (D2R) signaling. However, AAb influence on dopamine receptor D1 (D1R) activity is underexplored. We found evidence that suggests GAS-induced cross-reactive AAbs promote autoimmune encephalitis of the basal ganglia (BGE), a region of high dopamine receptor density. Here, we report a new mechanism whereby neuropsychiatric syndromes are distinguished from movement disorders by differences in D1R and D2R AAb titers, signaling, receiver operating characteristic (ROC) curves, and immunoreactivity with D1R and D2R autoreactive epitopes. D1R AAb signaling was observed through patient serum AAbs and novel patient-derived mAbs, which induced both D1R G protein- and -arrestin transduced signals. Furthermore, patient AAbs and mAbs enhanced D1R signaling mechanisms mediated by the neurotransmitter dopamine. Our findings suggest that AAb-mediated D1R signaling may contribute to the pathogenesis of neuropsychiatric sequelae and inform new options for diagnosis and treatment of GAS sequelae and related disorders.

Authors

Chandra M. Menendez, Jonathan Zuccolo, Susan E. Swedo, Sean Reim, Brian Richmand, Hilla Ben-Pazi, Abraham Kovoor, Madeleine W. Cunningham

The human milk oligosaccharide 3′sialyllactose reduces low-grade inflammation and atherosclerosis development in mice

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Abstract

Macrophages contribute to the induction and resolution of inflammation and play a central role in chronic low-grade inflammation in cardiovascular diseases caused by atherosclerosis. Human milk oligosaccharides (HMOs) are complex unconjugated glycans unique to human milk that benefit infant health and act as innate immune modulators. Here, we identify the HMO 3′sialyllactose (3′SL) as a natural inhibitor of Toll-Like Receptor (TLR) 4-induced low-grade inflammation in macrophages and endothelium. Transcriptome analysis in macrophages revealed that 3′SL attenuates mRNA levels of a selected set of inflammatory genes and promotes the activity of Liver X Receptor (LXR) and Sterol Regulatory Element-binding Protein-1 (SREBP). These acute anti-inflammatory effects of 3′SL were associated with reduced histone H3K27 acetylation at a subset of lipopolysaccharide (LPS)-inducible enhancers distinguished by preferential enrichment for CCCTC-binding factor (CTCF), Interferon Regulatory Factor 2 (IRF2), B-cell lymphoma 6 (BCL6), and other transcription factor recognition motifs. In a murine atherosclerosis model, both subcutaneous and oral administration of 3′SL significantly reduced atherosclerosis development and the associated inflammation. This study provides evidence that 3′SL attenuates inflammation by a transcriptional mechanism to reduce atherosclerosis development in the context of cardiovascular disease.

Authors

Ariane R. Pessentheiner, Nathanael J. Spann, Chloe A. Autran, Tae Gyu Oh, Kaare V. Grunddal, Joanna K.C. Coker, Chelsea D. Painter, Bastian Ramms, Austin W.T. Chiang, Chen-Yi Wang, Jason Hsiao, Yiwen Wang, Anthony Quach, Laela M. Booshehri, Alexandra Hammond, Chiara Tognaccini, Joanna Latasiewicz, Lisa Willemsen, Karsten Zengler, Menno P.J. de Winther, Hal M. Hoffman, Martin Philpott, Adam P. Cribbs, Udo Oppermann, Nathan E. Lewis, Joseph L. Witztum, Ruth Yu, Annette R. Atkins, Michael Downes, Ron M. Evans, Christopher K. Glass, Lars Bode, Philip L.S.M. Gordts

ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology

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Abstract

Grover disease is an acquired epidermal blistering disorder in which keratinocytes lose intercellular connections. While its pathologic features are well-defined, its etiology remains unclear and it lacks any FDA-approved therapy. Interestingly, Grover disease was a common adverse event in clinical trials for cancer using B-RAF inhibitors, but it remained unknown how B-RAF blockade compromised skin integrity. Here we identified ERK hyperactivation as a key driver of Grover disease pathology. We leveraged a fluorescent biosensor to confirm that B-RAF inhibitors, dabrafenib and vemurafenib, paradoxically activated ERK in human keratinocytes and organotypic epidermis, disrupting cell-cell junctions and weakening epithelial integrity. Consistent with clinical data showing that concomitant MEK blockade prevents Grover disease in patients receiving B-RAF inhibitors, we found that MEK inhibition suppressed ERK and rescued cohesion of B-RAF-inhibited keratinocytes. Validating these results, we demonstrated ERK hyperactivation in patient biopsies from vemurafenib-induced Grover disease, but also from spontaneous Grover disease, revealing a common etiology for both. Finally, in line with our recent identification of ERK hyperactivation in Darier disease, a genetic disorder with identical pathology to Grover disease, our studies uncovered that the pathogenic mechanisms of these two diseases converge on ERK signaling and support MEK inhibition as a therapeutic strategy.

Authors

Cory L. Simpson, Afua Tiwaa, Shivam A. Zaver, Christopher J. Johnson, Emily Y. Chu, Paul W. Harms, Johann E. Gudjonsson

GCN2 kinase activation mediates pulmonary vascular remodeling and pulmonary arterial hypertension

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Abstract

Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and remodeling that result in right heart failure. Recessive mutations of EIF2AK4 gene (encoding GCN2, General control nonderepressibe 2 kinase) are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients but rarely (approximately one percent) in PAH patients. The role of GCN2 kinase activation in the pathogenesis of PAH remains unclear. Here we show that GCN2 was hyperphosphorylated and activated in pulmonary vascular endothelial cells (ECs) of hypoxic mice, monocrotaline-treated rats, and PAH patients. Unexpectedly, loss of GCN2 kinase activity in Eif2ak4–/– mice with genetic disruption of the kinase domain induced neither PVOD nor PH but inhibited hypoxia-induced PH. RNA sequencing analysis suggested Endothelin-1 (Edn1) as a downstream target of GCN2. GCN2 mediated hypoxia-induced Edn1 expression in human lung ECs via HIF-2α. Restored Edn1 expression in ECs of Eif2ak4–/– mice partially reversed the reduced phenotype of hypoxia-induced PH. Furthermore, GCN2 kinase inhibitor A-92 treatment attenuated PAH in monocrotaline-treated rats. These studies demonstrate that GCN2 kinase activation mediates pulmonary vascular remodeling and PAH at least partially through Edn1. Thus, targeting GCN2 kinase activation is a promising therapeutic strategy for treatment of PAH in patients without EIF2AK4 loss of function mutations.

Authors

Maggie M. Zhu, Jingbo Dai, Zhiyu Dai, Yi Peng, You-Yang Zhao

S1P regulates intervertebral disc aging by mediating endoplasmic reticulum — mitochondrial calcium ion homeostasis

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Abstract

Mechanistically, S1P deficiency impeded COP II-mediated transport vesicles formation, which leads to proteins retention in the endoplasmic reticulum (ER) and subsequently ER distension. ER distension increased the contact between the ER and mitochondria, disrupting ER-to-mitochondria calcium flow, resulting in mitochondrial dysfunction and energy metabolism disturbance. Finally, using 2-APB to inhibit calcium ion channels and the senolytic drug dasatinib and quercetin (D + Q) partially rescued the aging and degenerative phenotypes caused by S1P deficiency. In conclusion, our findings suggest that S1P is a critical factor in causing IVDD in the process of aging and highlight the potential of targeting S1P as a therapeutic approach for age-related IVDD.

Authors

Bingjie Zheng, Xuyang Zhang, Xiangxi Kong, Jie Li, Bao Huang, Hui Li, Zhongyin Ji, Xiaoan Wei, Siyue Tao, Zhi Shan, Zemin Ling, Junhui Liu, Jian Chen, Fengdong Zhao

Extracellular vesicle transfer of miR-1 to adipose tissue modifies lipolytic pathways following resistance exercise

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Abstract

Extracellular vesicles (EVs) have emerged as important mediators of inter-tissue signaling and exercise adaptations. In this human study (n = 32), we provide evidence that muscle-specific microRNA-1 (miR-1) was transferred to adipose tissue via EVs following an acute bout of resistance exercise. Using a multi-model machine learning automation tool, we discovered muscle primary miR-1 transcript and CD63+ EV count in circulation as top explanatory features for changes in adipose miR-1 levels in response to resistance exercise. RNA-sequencing (RNA-seq) and in-silico prediction of miR-1 target genes identified caveolin 2 (CAV2) and tripartite motif containing 6 (TRIM6) as miR-1 target genes downregulated in the adipose tissue of a subset of participants with the highest increases in miR-1 levels following resistance exercise (n = 6). Overexpression of miR-1 in differentiated human adipocyte-derived stem cells downregulated these miR-1 targets and enhanced catecholamine-induced lipolysis. These data identify a potential EV-mediated mechanism by which skeletal muscle communicates to adipose tissue and modulates lipolysis via miR-1.

Authors

Benjamin I. Burke, Ahmed Ismaeel, Douglas E. Long, Lauren A. Depa, Peyton T. Coburn, Jensen Goh, Tolulope P. Saliu, Bonnie J. Walton, Ivan J. Vechetti, Bailey D. Peck, Taylor R. Valentino, C. Brooks Mobley, Hasiyet Memetimin, Dandan Wang, Brian S. Finlin, Philip A. Kern, Charlotte A. Peterson, John J. McCarthy, Yuan Wen

Deletion of GBA in neurons, but not microglia, causes neurodegeneration in a Gaucher mouse model

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Abstract

Gaucher disease, the most prevalent lysosomal storage disease, is caused by homozygous mutations at the GBA gene, responsible for encoding the enzyme glucocerebrosidase. Neuronopathic Gaucher disease is associated with microgliosis, astrogliosis, and neurodegeneration. However, the role that microglia, astrocytes, and neurons play in the disease remains to be determined. In the current study, we developed novel, inducible, cell-type specific GBA KO mice to understand the individual impacts of GBA deficiencies on microglia and neurons. GBA was conditionally knocked out either exclusively in microglia or neurons, or throughout the body. These novel mouse models were developed using a tamoxifen-inducible Cre system, with tamoxifen administration commencing at weaning. Microglia-specific GBA KO mice showed no signs of disease. However, the neuron-specific GBA KO resulted in a shortened lifespan, severe weight loss, and ataxia. These mice also had significant neurodegeneration, microgliosis, and astrogliosis accompanied by the accumulation of glucosylceramide and glucosylsphingosine, recapitulating Gaucher disease-like symptoms. These surprising findings reveal that, unlike the neuron-specific GBA deficiency, microglia-specific GBA deficiency alone does not induce disease. The novel neuronal Gaucher disease mouse model, with a median survival of 16 weeks, may be useful for future studies of pathogenesis and the evaluation of therapies.

Authors

Hannah B. D. Duffy, Colleen Byrnes, Hongling Zhu, Galina Tuymetova, Y. Terry Lee, Frances M. Platt, Richard L. Proia

Targeting heterogeneous tumor microenvironments in pancreatic cancer mouse models of metastasis by TGFβ depletion

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Abstract

The dual tumor-suppressive and promoting function of TGFβ signaling has made its targeting challenging. We hereby examined the effects of TGFβ depletion by AVID200/BMS-986416(TGFβ-TRAP), a TGFβ ligand trap, on the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) murine models with different organ-specific metastasis. Our study demonstrated that TGFβ-TRAP potentiates the efficacy of anti-PD-1 in a PDAC orthotopic murine model with liver metastasis tropism, significantly reducing liver metastases. We further demonstrated the heterogeneous response of cytotoxic effector T-cells to combination TGFβ-TRAP and anti-PD-1 treatment across several tumor models. Single-nuclear RNA-sequencing suggested that TGFβ-TRAP modulates cancer associated fibroblast (CAF) heterogeneity and suppresses neutrophil degranulation and CD4+ T-cell response to neutrophil degranulation. Ligand-receptor analysis indicated that TGFβ-TRAP may modulate the CCL5-CCR5 axis as well as co-stimulatory and checkpoint signaling from CAFs and myeloid cells. Notably, the most highly expressed ligands of CCR5 shifted from the immunosuppressive CCL5 to CCL7 and CCL8, which may mediate the immune agonist activity of CCR5 following TGFβ-TRAP and anti-PD-1 combination treatment. This study suggested that TGFβ depletion modulates CAF heterogeneity and potentially reprograms CAFs and myeloid cells into anti-tumor immune agonists in PDAC, supporting the validation of such effects in human specimen.

Authors

Sophia Y. Chen, Heng-Chung Kung, Birginia Espinoza, India Washington, Kai Chen, Jianxin Wang, Haley Zlomke, Michael A. Loycano, Rulin Wang, Michael Pickup, William R. Burns III, Juan Fu, William L. Hwang, Lei Zheng