Peptidylarginine deiminases 2 and 4 modulate innate and adaptive immune responses in TLR-7–dependent lupus

• DOI: 10.1172/jci.insight.124729
• Publication Date: 2018-12-05T16:01:32Z
• Authors: Yudong Liu; Yaíma L. Lightfoot; Nickie Seto; Carmelo Carmona-R...; Erica Moore; Rishi Goel; Liam O’Neil; Pragnesh Mistry; Victoria Hoffmann; Santanu Mondal; Padmavathy Nandha...; Katherine Gribbons; Stefania Dell’Orso; Kan Jiang; Paul R. Thompson; Hong-Wei Sun; Scott A. Coonrod; Mariana J. Kaplan
• Keywords: Neutrophil Extracellular Traps; Immune Dysregulation

The peptidylarginine deiminases PAD2 and PAD4 are implicated in the pathogenesis of several autoimmune diseases. may be pathogenic systemic lupus erythematosus (SLE) through its role neutrophil extracellular trap (NET) formation that promotes autoantigen externalization, immune dysregulation, organ damage. this enzyme mouse models autoimmunity remains unclear, as pan-PAD chemical inhibitors improve clinical phenotype, whereas PAD4-KO have given conflicting results. SLE has not been investigated. differential roles TLR-7-dependent were examined. Padi4-/- displayed decreased autoantibodies, type I IFN responses, cell activation, vascular dysfunction, NET immunogenicity. Padi2-/- mice showed abrogation Th subset polarization, with some disease manifestations reduced compared WT but to a lesser extent than mice. RNA sequencing analysis revealed distinct modulation immune-related pathways PAD-KO lymphoid organs. Human T cells express both PADs and, when exposed either or inhibitors, Th1 polarization. These results suggest targeting and/or activity modulates dysregulated responses effects innate adaptive immunity. Compounds target potential therapeutic cell-mediated