Role of Peptidyl arginine deiminase 4-dependent macrophage extracellular traps formation on Type 1 Diabetes pathogenesis

Abstract Excessive macrophage extracellular traps (METs) formation has been implicated in several autoimmune disease pathogenesis; however, its impact on Type 1 Diabetes (T1D) and related mechanisms remains enigmatic. Here, we demonstrated the pivotal role of peptidyl arginine deiminase 4 (PAD4) in driving profuse METs formation and macrophage M1 polarization in intestinal inflammation of non-obese diabetic (NOD) mice. Genetic knockout of PAD4 or adoptive transfer of METs alters the proportion of pro-inflammatory T cells in the intestine, subsequently influencing their migration to the pancreas. Combining RNA sequencing and CUT&Tag analysis we found activated PAD4 transcriptionally regulated CXCL10 expression. This study comprehensively investigated how excessive PAD4-mediated METs formation in the colon increases the aggravation of intestinal inflammation and pro-inflammatory T cells migration, and finally involves T1D progression, suggesting that inhibition METs formation may be a potential therapeutic target for T1D. Keywords: Type 1 Diabetes, Macrophage extracellular traps, Peptidyl arginine deiminase 4, CXCL10/CXCR3, Autoimmunity Article Highlights l The role of macrophage extracellular traps (METs) formation in the pathology of type 1 diabetes remains unclear. l We aim to investigate the impact of METs formation on intestinal inflammation and its subsequent effect on the pathogenesis of Type 1 diabetes in NOD mice. l Activated PAD4 facilitates METs formation and transcriptionally regulates CXCL10 expression, leading to accelerated type 1 diabetes through the activation and migration of pro-inflammatory T cells via the gut-pancreas axis. l Findings suggest that targeting PAD4-mediated METs formation could emerge as a potential therapeutic strategy.