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
Choline kinase (ChoK) has been well documented as a major enzyme involved in the anomalous cellular lipid metabolic profile of chronic inflammatory disorders. However, new research has now been unveiled that helps us to better understand how changes in lipid metabolism influence the transformational phenotype, drug resistance, and antiapoptotic characteristics of invasive cells, leading to rheumatoid arthritis (RA) disease progression. It is still unknown how ChoK modulates the lipid metabolic aberrations that may promote altered cell phenotype and functionality in RA. Herein, we review the current understanding of ChoK's role in altered metabolism in diverse cell types involved in RA progression, and for the first time, we take a step forward to complete the puzzle and summarise striking facts that link choline metabolism to its transformed phenotype, in order to postulate ChoK as a robust therapeutic target in RA. This review forms a foundation on which ChoK can be tackled as a potential biomarker, opening doors for RA diagnosis and prognosis. It frameworks several ChoK inhibitors that rewire the lipid metabolic profile in the inflammatory disease landscape and envisages its being translated to clinics.
