Xie et al. report that aberrant ciliary redistribution of phospholipid PI(4,5)P2 and filament-actin are necessary for olfactory cilia disassembly and contribute to the pathogenesis of Bardet–Biedl syndrome. Image credit: Nemes Laszlo/Shutterstock.
BACKGROUND. Systemic sclerosis (SSc) is an autoimmune, connective tissue disease characterized by vasculopathy and fibrosis of the skin and internal organs. METHODS. We randomized 15 participants with early diffuse cutaneous SSc to tofacitinib 5 mg twice a day or matching placebo in a Phase I/II double-blind, placebo-controlled trial. The primary outcome measure was safety and tolerability at or before Week 24. In order to understand the changes in gene expression associated with tofacitinib treatment in each skin cell populations, we compared single cell gene expression in punch skin biopsies obtained at baseline and 6 weeks following the initiation of treatment. RESULTS. Tofacitinib was well tolerated; there were no participants, who experienced Grade 3 or higher adverse effects (AEs) before or at Week 24. Trends in efficacy outcome measures favored tofacitnib. Baseline gene expression in fibroblast and keratinocyte subpopulations indicates interferon (IFN) activated gene expression. Tofacitinib inhibited IFN-regulated gene expression in the SFRP2/DPP4 fibroblasts (progenitors of myofibroblasts) and MYOC and CCL19, representing adventitial fibroblasts (p< 0.05), as well as in the basal and keratinized layers of the epidermis. Gene expression in macrophages and dendritic cells indicated inhibition of STAT3 by tofacitinib (p<0.05). No clinically meaningful inhibition of T cells and endothelial cells in the skin tissue was observed. CONCLUSION. These results indicate that mesenchymal and epithelial cells of a target organ in SSc, not the infiltrating lymphocytes, may be the primary focus for therapeutic effects of a janus kinase inhibitor. TRIAL REGISTRATION. clinicaltrials.gov NCT03274076. FUNDING SOURCE. This was an investigator-initiated trial designed by the Sponsor and the steering committee. The industry funder, Pfizer, had no role in collecting, analyzing, and interpreting the data. The manuscript was drafted by the authors and was reviewed by Pfizer Inc. before final submission. No medical writer was involved in creating the manuscript. DK was supported by NIH/NIAMS R01 AR070470 and NIH/NIAMS K24 AR063120. JMK, JEG, LCT are supported by the Taubman Medical Research Institute and NIH-P30 AR075043. LCT was also supported by NIH/NIAMS K01AR072129. The corresponding author had full access to all data congregates in the study and made the final decision to submit the manuscript for publication.
Dinesh Khanna, Cristina M. Padilla, Lam C. Tsoi, Vivek Nagaraja, Puja Khanna, Tracy Tabib, J. Michelle Kahlenberg, Amber Young, Suiyuan Huang, Johann e. Gudjonsson, David A. Fox, Robert Lafyatis
B-lymphocytes have long been recognized for their critical contributions to adaptive immunity, providing defense against pathogens through cognate antigen presentation to T cells and antibody production. More recently appreciated is that B cells are also integral in securing self-tolerance; this has led to interest in their therapeutic application to down-regulate unwanted immune responses such as transplant rejection. In this study, we found that PMA and ionomycin-activated mouse B cells acquire regulatory properties following stimulation through Toll-like receptor (TLR)4/TLR9 receptors (Bregs-TLR). Bregs-TLR efficiently inhibited T cell proliferation in vitro and prevented allograft rejection. Unlike most reported Breg activities, the inhibition of alloimmune responses by Bregs-TLR relied on the expression of TGF-βand not IL-10. In vivo, Bregs-TLR interrupted donor-specific T cell expansion and induced regulatory T cells in a TGF-β dependent manner. RNA-seq analyses corroborated the involvement of TGF-β pathways in Breg-TLR function, identified potential gene pathways implicated in preventing graft rejection, and suggested new targets to foster Breg regulation.
Kang Mi Lee, Qiang Fu, Guoli Huai, Kevin Deng, Ji Lei, Lisa Kojima, Divyansh Agarwal, Peter Van Galen, Shoko Kimura, Naoki Tanimine, Laura Washburn, Heidi Yeh, Ali Naji, Charles G. Rickert, Christian LeGuern, James F. Markmann
Junctional adhesion molecule-A (JAM-A) is expressed in several cell types including epithelial and endothelial cells as well as some leukocytes. In intestinal epithelial cells (IEC), JAM-A localizes to cell junctions and plays a role in regulating barrier function. In vitro studies with model cell lines have shown that JAM-A contributes to IEC migration, however in vivo studies investigating the role of JAM-A in cell migration-dependent processes such as mucosal wound repair have not been performed. In this study, we developed an inducible intestinal epithelial-specific JAM-A knockdown mouse model (Jam-aER-ΔIEC). While acute induction of IEC-specific loss of JAM-A did not result in spontaneous colitis, such mice had significantly impaired mucosal healing after chemically induced colitis and after biopsy colonic wounding. In vitro primary cultures of JAM-A deficient IEC demonstrated impaired migration in wound healing assays. Mechanistic studies revealed that JAM-A stabilizes formation of protein signaling complexes containing Rap1A/Talin/β1-integrin at focal adhesions of migrating IECs. Loss of JAM-A in primary IEC led to decreased Rap1A activity and protein levels of Talin and β1-integrin and a reduction in focal adhesion structures. These findings suggest that epithelial JAM-A plays a critical role in controlling mucosal repair in vivo through dynamic regulation of focal adhesions
Shuling Fan, Kevin Boerner, Chithra K. Muraleedharan, Asma Nusrat, Miguel Quiros, Charles A. Parkos
Plasmacytoid dendritic cells (pDCs) perform dual proinflammatory and immunosuppressive roles. We recently reported the potential of pDC therapy for treatment of intractable acute liver failure. However, establishment of efficient methods to deliver pDCs to the liver is essential for future clinical therapeutic applications. The present study demonstrates a higher abundance of liver and peripheral blood pDCs in mice lacking the C-C motif chemokine receptor 9 (CCR9), a pDC gut-homing receptor, than that in wild-type (WT) mice. Adoptive pDC transfer resulted in a higher efficiency of Ccr9-/- pDC migration to the liver than that to the original target organ, the small intestine, compared with that of WT pDCs. Further, Ccr9-/- pDCs consistently migrated efficiently to the concanavalin A-induced inflamed liver, and exerted a more effective immunosuppressive effect, resulting in better protection against acute liver inflammation than that demonstrated by WT pDCs. These findings highlight the therapeutic potential of the manipulation of CCR9 axis as a novel approach to improve migration of immunosuppressive pDCs to the liver in order to exploit their beneficial effects in acute liver disease.
Yuzo Koda, Nobuhiro Nakamoto, Po-Sung Chu, Toshiaki Teratani, Akihisa Ueno, Takeru Amiya, Nobuhito Taniki, Sayako Chiba, Kentaro Miyamoto, Michiie Sakamoto, Takanori Kanai
Immune checkpoint blockade (ICB) therapy has achieved breakthroughs in the treatment of advanced non-small cell lung cancer (NSCLC). Nevertheless, the low response due to immuno-cold tumor microenvironment (TME) largely limits the application of ICB therapy. Based on the glycolytic/cholesterol synthesis axis, a stratification framework for EGFR wild-type NSCLC was developed to summarize the metabolic features of immuno-cold and immuno-hot tumors. The cholesterol subgroup displays the worst prognosis in immuno-cold NSCLC with significant enrichment of the cholesterol gene signature, indicating targeting cholesterol synthesis is essential for the therapy for immuno-cold NSCLC. Statin, the inhibitor for cholesterol synthesis, can suppress the aggressiveness of NSCLC in vitro and in vivo and also drastically reverse immuno-cold to an inflamed phenotype in vivo which exhibited a higher response to ICB therapy. Moreover, both our in-house data and meta-analysis further support that statin can significantly enhance ICB efficacy. In terms of preliminary mechanisms, statin could transcriptionally inhibit PD-L1 expression and induce ferroptosis in NSCLC cells. Overall, we reveal the significance of cholesterol synthesis in NSCLC and demonstrate the improved therapeutic efficacy of ICB in combination with statin. These findings could provide a innovative clinical insight to treat NSCLC patients with immuno-cold tumors.
Wenjun Mao, Yun Cai, Danrong Chen, Guanyu Jiang, Yongrui Xu, Ruo Chen, Fengxu Wang, Xuehai Wang, Mingfeng Zheng, Xinyuan Zhao, Jie Mei