2. Academic Validation
  3. IL-17A/IL-17RA interaction blockade sensitizes synovial macrophages to efferocytosis and PD-L1 signaling via rewiring STAT-3/ADAM17/MERTK axis in rheumatoid arthritis animal model

IL-17A/IL-17RA interaction blockade sensitizes synovial macrophages to efferocytosis and PD-L1 signaling via rewiring STAT-3/ADAM17/MERTK axis in rheumatoid arthritis animal model

  • Int Immunopharmacol. 2024 Jul 30:136:112343. doi: 10.1016/j.intimp.2024.112343.
Snigdha Samarpita 1,  Susmita Srivastava 2,  Manupati Srikanth 2,  Ann Miriam Jose 2,  Arulkumaran Rithvik 2,  Mahaboobkhan Rasool 3
Affiliations

Affiliations

  • 1 Immunopathology Lab, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632 014, Tamil Nadu, India; Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
  • 2 Immunopathology Lab, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632 014, Tamil Nadu, India.
  • 3 Immunopathology Lab, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632 014, Tamil Nadu, India. Electronic address: mkr474@gmail.com.
PMID: 38810305 DOI: 10.1016/j.intimp.2024.112343
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.

Keywords

Cyanidin; Efferocytosis; Interleukin-17A; PD-L1; Rheumatoid arthritis.

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