CXCL10 secreted by SPRY1-deficient epidermal keratinocytes fuels joint inflammation in psoriatic arthritis via CD14 signaling

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Abstract

Psoriatic arthritis (PsA) is a multifaceted chronic inflammatory disease affecting the skin, joints, and entheses, and is a major comorbidity of psoriasis. Most patients with PsA present with psoriasis before articular involvement, however, the molecular and cellular mechanisms underlying the link between cutaneous psoriasis and PsA are poorly understood. Here, we found that epidermal-specific SPRY1-deficient mice spontaneously developed PsA-like inflammation involving both the skin and joints. Excessive CXCL10 was secreted by SPRY1-deficient epidermal keratinocytes through enhanced activation of JAK1/2-STAT1 signaling, and CXCL10 blockade attenuated PsA-like inflammation. Of note, CXCL10 was found to bind to CD14, but not CXCR3, to promote the TNF𝜶 production of periarticular CD14hi macrophages via PI3K/AKT and NF-κB signaling pathways. Collectively, this study reveals that SPRY1 deficiency in the epidermis is sufficient to drive both skin and joint inflammation, and identifies keratinocyte-derived CXCL10 and periarticular CD14hi macrophages as critical links in the skin-joint crosstalk leading to PsA. This keratinocyte SPRY1-CXCL10-periarticular CD14hi macrophages-TNFα axis provides valuable insights into the mechanisms underlying the transition from psoriasis to PsA and suggests potential therapeutic targets for preventing this progression.

Authors

Fan Xu, Ying-Zhe Cui, Xing-Yu Yang, Yu-Xin Zheng, Xi-Bei Chen, Hao Zhou, Zhao-Yuan Wang, Yuan Zhou, Yi Lu, Ying-Ying Li, Li-Ran Ye, Ni-Chang Fu, Si-Qi Chen, Xue-Yan Chen, Min Zheng, Yong Yang, Xiao-Yong Man

The microRNA miR-30a blocks adipose tissue fibrosis accumulation in obesity

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Abstract

White adipose tissue (WAT) fibrosis occurring in obesity contributes to the inflammatory and metabolic co-morbidities of insulin resistance and type 2 diabetes, yet the mechanisms involved remain poorly understood. Here, we report a role for the broadly conserved microRNA miR-30a as a regulator of WAT fibrosis and systemic glucose metabolism. Mice modified to express miR-30a at elevated levels in adipose tissues maintain insulin sensitivity coupled with reduced fatty liver disease when fed high fat diet. These effects were attributable to cell-autonomous functions of miR-30a that potently increase expression of adipocyte-specific genes. Proteomic screening revealed miR-30a limits pro-fibrotic programs in subcutaneous WAT, at least in part, by repressing PAI-1, a dominant regulator of fibrinolysis and biomarker of insulin resistance. Conversely, mouse adipocytes lacking miR-30a exhibited greater expression of fibrosis markers with disrupted cellular metabolism. Lastly, miR-30a expression negatively correlates with PAI-1 levels in subcutaneous WAT from people with obesity, further supporting an anti-fibrotic role for miR-30a. Together, these findings uncover miR-30a as a critical regulator of adipose tissue fibrosis that predicts metabolically healthy obesity in people and mice.

Authors

Pradip K. Saha, Robert Sharp, Aaron R. Cox, Rabie Habib, Michael J. Bolt, Jessica B. Felix, Claudia E. Ramirez Bustamante, Xin Li, Sung Yun Jung, Kang Ho Kim, Kai Sun, Huaizhu Wu, Samuel Klein, Sean M. Hartig

FGFR3-induced Y158 PARP1 phosphorylation promotes PARP-inhibitor resistance via BRG1/MRE11-mediated DNA repair in breast cancer models

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Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are used to treat BRCA-mutated (BRCAm) cancer patients; however, resistance has been observed. Therefore, biomarkers to indicate PARPi resistance and combination therapy to overcome that are urgently needed. We identified a high prevalence of activated FGF receptor 3 (FGFR3) in BRCAm triple-negative breast cancer (TNBC) cells with intrinsic and acquired PARPi resistance. FGFR3 phosphorylated PARP1 at tyrosine 158 (Y158) to recruit BRG1 and prolong chromatin-loaded MRE11, thus promoting homologous recombination (HR) to enhance PARPi resistance. FGFR inhibition prolonged PARP trapping and synergized with PARPi in vitro and in vivo. High-level PARP1 Y158 phosphorylation (p-Y158) positively correlated with PARPi resistance in TNBC patient-derived xenograft models, and in PARPi-resistant TNBC patient tumors. These findings reveal that PARP1 p-Y158 facilitates BRG1-mediated HR to resolve the PARP-DNA complex, and PARP1 p-Y158 may indicate PARPi resistance that can be relieved by combining FGFR inhibitors (FGFRi) with PARPi. In summary, we show that FGFRi restores PARP trapping and PARPi antitumor efficacy in PARPi-resistant breast cancer by decreasing HR through the PARP1 p-Y158/BRG1/MRE11 axis, suggesting that PARP1 p-Y158 is a biomarker for PARPi resistance that can be overcome by combining FGFRi with PARPi.

Authors

Mei-Kuang Chen, Hirohito Yamaguchi, Yuan Gao, Weiya Xia, Jeffrey T. Chang, Yu-Chun Hsiao, Tewodros W. Shegute, Zong-Shin Lin, Chen-Shiou Wu, Yu-Han Wang, Jennifer K. Litton, Qingqing Ding, Yongkun Wei, Yu-Yi Chu, Funda Meric-Bernstam, Helen Piwnica-Worms, Banu Arun, Jordi Rodon Ahnert, Jinsong Liu, Jun Yao, Wei-Chao Chang, Hung-Ling Wang, Coya Tapia, Constance T. Albarracin, Khandan Keyomarsi, Shao-Chun Wang, Ying-Nai Wang, Gabriel N. Hortobagyi, Chunru Lin, Liuqing Yang, Dihua Yu, Mien-Chie Hung

Mutant THAP11 causes cerebellar neurodegeneration and triggers TREM2-mediated microglial activation in mice

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Abstract

Abnormal expansions of CAG trinucleotide repeat within specific gene exons give rise to polyglutamine (polyQ) diseases, a family of inherited disorders characterized by late-onset neurodegeneration. Recently, a new type of polyQ disease was identified and named spinocerebellar ataxia 51 (SCA51). SCA51 is caused by polyQ expansion in THAP11, an essential transcription factor for brain development. The pathogenesis of SCA51, particularly how mutant THAP11 with polyQ expansion contributes to neuropathology, remains elusive. Our study of mouse and monkey brains revealed that THAP11 expression is subject to developmental regulation, showing enrichment in the cerebellum. However, knocking down endogenous THAP11 in adult mice does not affect neuronal survival. In contrast, expressing mutant THAP11 with polyQ expansion leads to pronounced protein aggregation, cerebellar neurodegeneration, and motor deficits, indicating that gain-of-function mechanisms are central to SCA51 pathogenesis. We discovered activated microglia expressing TREM2 in the cerebellum of a newly developed SCA51 knock-in mouse model. Mechanistically, mutant THAP11 enhances the transcription of TREM2, leading to its upregulation. The loss of TREM2 or depletion of microglia mitigates neurodegeneration induced by mutant THAP11. Our study offers the first mechanistic insights into the pathogenesis of SCA51, highlighting the role of TREM2-mediated microglial activation in SCA51 neuropathology.

Authors

Eshu Ruan, Jingpan Lin, Zhao Chen, Qianai Sheng, Laiqiang Chen, Jiating He, Xuezhi Duan, Yiyang Qin, Tingting Xing, Sitong Yang, Mingtian Pan, Xiangyu Guo, Peng Yin, Xiao-Jiang Li, Hong Jiang, Shihua Li, Su Yang

Tumor microenvironment of non-small cell lung cancer impairs immune cell function among people with HIV

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Abstract

Lung cancer is the leading cause of cancer mortality among people with HIV (PWH), with increased incidence and poor outcomes. This study explored whether the tumor microenvironment (TME) of HIV-associated non-small cell lung cancer (NSCLC) limits tumor-specific immune responses. With a matched cohort of NSCLC from PWH and people without HIV (PWOH), we used imaging mass cytometry, linear mixed effects model and AI-based pageRank mathematical algorithm based on spectral graph theory to demonstrate that HIV-associated tumors demonstrate differential distribution of tumor infiltrating CD8+ and CD4+ T cells, enriched for the expression of PD-1 and Lag-3, as well as activation and proliferation markers. We also demonstrate higher expression of immunoregulatory molecules (PD-L1, PD-L2, B7-H3, B7-H4, IDO1 and VISTA), among tumor-associated macrophages. Discrimination of cells between tumors from PWH versus PWOH was confirmed by spectral graph theory with 84.6% accuracy. Furthermore, we noted differences in spatial orientation of immune cells within the TME of PWH compared to PWOH. Additionally, cells from PWH, compared to PWOH, exhibited decreased tumor killing when exposed to HLA-matched NSCLC cell lines. In conclusion, our study demonstrates that the HIV-associated tumor microenvironment sustains a unique immune landscape, with evidence of immune cells with enhanced immunoregulatory phenotypes and impaired anti-tumor responses, with implications for response to immune checkpoint blocker therapies.

Authors

Shruti S. Desai, Syim Salahuddin, Ramsey Yusuf, Kishu Ranjan, Jianlei Gu, Lais Osmani, Ya-Wei Eileen Lin, Sameet Mehta, Ronen Talmon, Insoo Kang, Yuval Kluger, Hongyu Zhao, Kurt A. Schalper, Brinda Emu

Polygenic modifiers impact penetrance and expressivity in telomere biology disorders

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Abstract

BACKGROUND. Telomere biology disorders (TBDs) exhibit incomplete penetrance and variable expressivity, even among individuals harboring the same pathogenic variant. We assessed whether common genetic variants associated with telomere length combine with large-effect variants to impact penetrance and expressivity in TBDs. METHODS. We constructed polygenic scores (PGS) for telomere length in the UK Biobank to quantify common variant burden, and assessed the PGS distribution across patient cohorts and biobanks to determine whether individuals with severe TBD presentations have increased polygenic burden causing short telomeres. We also characterized rare TBD variant carriers in the UK Biobank. RESULTS. Individuals with TBDs in cohorts enriched for severe pediatric presentations have polygenic scores predictive of short telomeres. In the UK Biobank, we identify carriers of pathogenic TBD variants who are enriched for adult-onset manifestations of TBDs. Unlike individuals in disease cohorts, the PGS of adult carriers do not show a common variant burden for shorter telomeres, consistent with the absence of childhood-onset disease. Notably, TBD variant carriers are enriched for idiopathic pulmonary fibrosis diagnoses, and telomere length PGS stratifies pulmonary fibrosis risk. Finally, common variants affecting telomere length were enriched in enhancers regulating known TBD genes. CONCLUSION. Common genetic variants combine with large-effect causal variants to impact clinical manifestations in rare TBDs. These findings offer a framework for understanding phenotypic variability in other presumed monogenic disorders. FUNDING. This work was supported by National Institutes of Health grants R01DK103794, R01HL146500, R01CA265726, R01CA292941, and the Howard Hughes Medical Institute.

Authors

Michael Poeschla, Uma P. Arora, Amanda Walne, Lisa J. McReynolds, Marena R. Niewisch, Neelam Giri, Logan P. Zeigler, Alexander Gusev, Mitchell J. Machiela, Hemanth Tummala, Sharon A. Savage, Vijay G. Sankaran

Immune cells promote paralytic disease in mice infected with enterovirus D68

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Abstract

Enterovirus D68 (EV-D68) is associated with acute flaccid myelitis (AFM), a poliomyelitis-like illness causing paralysis in young children. However, mechanisms of paralysis are unclear, and antiviral therapies are lacking. To better understand EV-D68 disease, we inoculated newborn mice intracranially to assess viral tropism, virulence, and immune responses. Wild-type (WT) mice inoculated intracranially with a neurovirulent strain of EV-D68 showed infection of spinal cord neurons and developed paralysis. Spinal tissue from infected mice revealed increased chemokines, inflammatory monocytes, macrophages, and T cells relative to controls, suggesting that immune cell infiltration influences pathogenesis. To define the contribution of cytokine-mediated immune cell recruitment to disease, we inoculated mice lacking CCR2, a receptor for several EV-D68-upregulated cytokines, or RAG1, which is required for lymphocyte maturation. WT, Ccr2-/-, and Rag1-/- mice had comparable viral titers in spinal tissue. However, Ccr2-/- and Rag1-/- mice were significantly less likely to be paralyzed relative to WT mice. Consistent with impaired T cell recruitment to sites of infection in Ccr2-/- and Rag1 -/- mice, antibody-mediated depletion of CD4+ or CD8+ T cells from WT mice diminished paralysis. These results indicate that immune cell recruitment to the spinal cord promotes EV-D68-associated paralysis and illuminate new targets for therapeutic intervention.

Authors

Mikal A. Woods Acevedo, Jie Lan, Sarah Maya, Jennifer E. Jones, Isabella E. Bosco, John V. Williams, Megan C. Freeman, Terence S. Dermody

Hyperinsulinemia-induced upregulation of adipocyte TPH2 contributes to peripheral serotonin production, metabolic dysfunction, and obesity

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Abstract

Tryptophan hydroxylase (TPH) is a rate-limiting enzyme for serotonin or 5-hydroxytryptamine (5-HT) synthesis. Previously, adipocyte TPH1 has been linked to increased adipose 5-HT, reduced BAT thermogenesis, and obesity. However, the role of TPH2, a neural isoform highly expressed in obese adipose tissue, is unknown. Here, we report that adipose tissue expression of TPH2 is significantly elevated in both diet-induced obese (DIO) and ob/ob mice, as well as in obese humans. In high-fat diet (HFD)-fed mice, adipocyte TPH2 deficiency improves DIO-induced metabolic complications, enhances BAT thermogenesis, and increases intestinal energy harvesting efficiency without affecting adiposity. Conversely, TPH2 overexpression in epididymal adipocytes of chow-fed mice raises adipose and plasma 5-HT levels, suppresses BAT thermogenesis, and exacerbates obesity and metabolic dysfunction. We found that obesity-induced hyperinsulinemia upregulates adipocyte TPH2 expression via activation of mechanistic target of rapamycin complex 1 (mTORC1) and sterol regulatory element binding protein 1 (SREBP1). In humans, TPH2 mRNA levels in subcutaneous adipose tissue, but not TPH1, is positively correlated with fasting plasma insulin concentrations. In summary, our study demonstrates that obesity-associated increases in adipocyte TPH2 can regulate distal tissue physiology and energy metabolism, suggesting that TPH2 could be a potential therapeutic target for obesity and its associated complications.

Authors

Brian I. Park, Andrew R. Reeves, Ying Zhu, Robin A. Wilson, Sophia C. Fernandes, Kimberly K. Buhman, Kelli A. Lytle, Michael D. Jensen, Andrew S. Greenberg

Chemotaxis overrides killing response in alloreactive cytotoxic T-cells providing vascular immune privilege during cellular rejection

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Abstract

Graft endothelial cells (ECs) express donor alloantigens and encounter cytotoxic T lymphocytes (CTLs) but are generally spared during T cell-mediated rejection (TCMR), which predominantly affects epithelial structures. The mechanisms underlying this vascular immune privilege are unclear. Transcriptomic analyses and endothelial-mesenchymal transition assessments confirmed that the graft endothelium is preserved during TCMR. Co-culture experiments revealed that endothelial and epithelial cells are equally susceptible to CTL-mediated lysis, ruling out cell-intrinsic protection. Intravital microscopy of murine kidney grafts and single-cell RNA sequencing of human renal allografts demonstrated that CTL interactions with ECs are transient compared to epithelial cells. This disparity is mediated by a chemotactic gradient produced by graft stromal cells, guiding CTLs away from ECs toward epithelial targets. In vitro, chemotaxis overrode TCR-induced cytotoxicity, preventing endothelial damage. Finally, analysis of TCMR biopsies revealed that disruption of the chemotactic gradient correlates with endothelialitis lesions, linking its loss to vascular damage. These findings challenge the traditional view of cell-intrinsic immune privilege, proposing a cell-extrinsic mechanism where chemotaxis preserves graft vasculature during TCMR. This mechanism may have implications beyond transplantation, highlighting its role in maintaining vascular integrity across pathological conditions.

Authors

T. Barba, M. Oberbarnscheidt, G. Franck, C. Gao, S. This, M. Rabeyrin, C. Roufosse, L. Moran, A. Koenig, V. Mathias, C. Saison, V. Dubois, N. Pallet, D. Anglicheau, B. Lamarthée, A. Hertig, E. Morelon, A Hot, H. Paidassi, T. Defrance, A. Nicoletti, J.P. Duong-Van-Huyen, Y. Xu-Dubois, F.G. Lakkis, O. Thaunat

Splicing of erythroid transcription factor is associated with therapeutic response in myelodysplastic syndromes

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Abstract

Anemia is the primary clinical manifestation of myelodysplastic syndromes (MDS), but the molecular pathogenesis of ineffective erythropoiesis remains incompletely understood. Luspatercept, an activin receptor 2B (ACVRIIB-Fc) ligand trap, has been approved to treat anemia, however its molecular mechanism of action is unclear. We found that the ACVR2B, its ligand GDF11, and effector, SMAD2, are upregulated in MDS patient samples. GDF11 inhibited human erythropoiesis in vitro and caused anemia in zebrafish, effects that were abrogated by luspatercept. Upon GDF11 stimulation of human erythroid progenitors, SMAD2 binding occurred in the erythroid regulatory regions, including at GATA1 intron. Intronic SMAD2 binding led to skipping of exon 2 of GATA1, resulting in a shorter, hypomorphic isoform (GATA1s). CRISPR deletion of the SMAD2 binding intronic region decreased GATA1s production upon GDF11 stimulation. Expression of gata1s in a mouse model led to anemia, rescued by a murine ActRIIB-Fc (RAP-536). Finally, RNA-seq analysis of samples from the Phase 3 MEDALIST trial revealed that responders to Luspatercept had a higher proportion of GATA1s compared to non-responders. Moreover, the increase RBCs post-treatment was linked to a relative decrease in GATA1s isoform. Our study indicates that GDF11-mediated SMAD2 activation results in an increase in functionally impaired GATA1 isoforms, consequently contributing to anemia and influencing responses to Luspatercept in MDS.

Authors

Srinivas Aluri, Te Ling, Ellen Fraint, Samarpana Chakraborty, Kevin Zhang, Aarif Ahsan, Leah Kravets, Gowri Poigaialwar, Rongbao Zhao, Kith Pradhan, Anitria Cotton, Kimo Bachiashvili, Jung-In Yang, Anjali Budhathoki, Beamon Agarwal, Shanisha Gordon-Mitchell, Milagros Carbajal, Srabani Sahu, Jacqueline Boultwood, Andrea Pellagatti, Ulrich Steidl, Amittha Wickrema, Satish Nandakumar, Aditi Shastri, Rajasekhar N.V.S. Suragani, Teresa V. Bowman, John D. Crispino, Sadanand Vodala, Amit Verma