ABSTRACT
Defective clearance of apoptotic cells due to impaired efferocytosis sustains error in self-tolerance that exacerbates rheumatoid arthritis (RA). However, the molecular determinant that directly or specifically impairs efferocytosis in RA is not yet studied. We identified a new perspective that IL-17A significantly impedes efferocytosis via preferential activation of the JAK/STAT-3/ADAM17 signaling axis. In contrast, disruption of the IL-17A/IL-17RA interaction using cyanidin or silencing of IL-17RA obstructed JAK/STAT-3 activation that further abolished ADAM17 expression. Subsequent depletion of ADAM17 inhibited the shedding of Mer tyrosine kinase receptor (MERTK), which significantly increased apoptotic cell intake and restored efferocytosis in adjuvant-induced arthritic (AA) model. Concomitantly, the amplification of the efferocytosis process due to IL-17A/IL-17RA interaction disruption was sensitive to mitochondrial fission mediated via Drp-1 phosphorylation downstream of STAT-3 inhibition. As expected, cyanidin treated AA synovial macrophages that exhibited increased efferocytosis demonstrated a phenotypic shift towards CD163 anti-inflammatory phenotype in a STAT-5 dependent manner. Similar results were obtained in IL-17A-sensitized AA synovial macrophages treated with S3I-201 (a STAT-3 inhibitor) indicating that IL-17A influences efferocytosis via the STAT-3 pathway. In view of our previous work where cyanidin restored Th17/Treg balance, our present investigation fulfils a critical gap by providing scientific validation that cyanidin escalated PD-L1 expression during the efferocytosis process that could have impacted the restoration of Th17/Treg balance in an AA model. Together, these data corroborate the hypothesis that IL-17A signaling can impair efferocytosis via regulating STAT-3/ADAM17/FL-MERTK axis and that its inhibition can amplify a pro-resolution signal against RA progression.
Subject(s)
Arthritis, Rheumatoid , B7-H1 Antigen , Interleukin-17 , Macrophages , Receptors, Interleukin-17 , STAT3 Transcription Factor , Signal Transduction , Interleukin-17/metabolism , Animals , STAT3 Transcription Factor/metabolism , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/metabolism , Arthritis, Rheumatoid/drug therapy , Macrophages/immunology , Macrophages/metabolism , Macrophages/drug effects , B7-H1 Antigen/metabolism , Mice , Receptors, Interleukin-17/metabolism , Receptors, Interleukin-17/genetics , Anthocyanins/pharmacology , Arthritis, Experimental/immunology , Humans , Disease Models, Animal , Phagocytosis/drug effects , Male , Synovial Membrane/immunology , Synovial Membrane/pathology , Mice, Inbred C57BL , Apoptosis/drug effects , EfferocytosisABSTRACT
Psoriasis is a paradigmatic condition characterised by a heightened autoimmune response and chronic inflammation. However, the exact nature and the pathological causes behind it are still unknown. Growing evidence suggest dysregulated cytokine network as a result of over-activated T cells and plasmacytoid dendritic cells (pDCs) as the critical drivers in the development of psoriasis. In the present study, we aimed to investigate the therapeutic efficacy of 3,3'-diindolylmethane (DIM) on pDC activation and Th17 cell development in imiquimod (IMQ)-induced psoriasis mice. Our in vitro research investigated the IRF-7 signalling in pDCs that explained the reduced expression of the transcription factor IRF-7 responsible for pDC activation as a result of DIM treatment. Concurrently, DIM treatment decreased the release of Th17 cell polarising cytokines (IFN-α, IL-23, and IL-6) by pDCs which validated a reduction in differentiated pathogenic Th17 cell population and associated cytokine IL-17A in IMQ-induced psoriatic mice. Thus, our recent findings provide therapeutic evidence in targeting the early potential contributors for psoriasis treatment by preventing IRF-7-mediated pDC activation and Th17 cell development in IMQ-induced psoriasis mice.
ABSTRACT
The intriguing scientific relationship between autoimmunity and cancer immunology have been traditionally indulged to throw spotlight on novel pathological targets. Understandably, these "slowly killing" diseases are on the opposite ends of the immune spectrum. However, the immune regulatory mechanisms between autoimmunity and cancer are not always contradictory and sometimes mirror each other based on disease stage, location, and timepoint. Moreover, the blockade of immune checkpoint molecules or signalling pathways that unleashes the immune response against cancer is being leveraged to preserve self-tolerance and treat many autoimmune disorders. Therefore, understanding the common crucial factors involved in cancer is of paramount importance to paint the autoimmune disease spectrum and validate novel drug candidates. In the current review, we will broadly describe how ZEB1, or Zinc-finger E-box Binding Homeobox 1, reinforces immune exhaustion in cancer or contributes to loss of self-tolerance in auto-immune conditions. We made an effort to exchange information about the molecular pathways and pathological responses (immune regulation, cell proliferation, senescence, autophagy, hypoxia, and circadian rhythm) that can be regulated by ZEB1 in the context of autoimmunity. This will help untwine the intricate and closely postured pathogenesis of ZEB1, that is less explored from the perspective of autoimmunity than its counterpart, cancer. This review will further consider several approaches for targeting ZEB1 in autoimmunity.
