School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
Center for Translational Research in Infection and Inflammation, Tulane University, New Orleans, LA.
Diabetes. 2024 Nov 1;73(11):1862-1874. doi: 10.2337/db23-1000.
Excessive formation of macrophage extracellular trap (MET) has been implicated in several autoimmune disease pathogeneses; however, its impact on type 1 diabetes (T1D) and related mechanisms remains enigmatic. We demonstrated the pivotal role of peptidyl arginine deiminase 4 (PAD4) in driving profuse MET formation and macrophage M1 polarization in intestinal inflammation in NOD mice. Genetic knockout of PAD4 or adoptive transfer of METs altered the proportion of proinflammatory 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 MET formation in the colon increases the aggravation of intestinal inflammation and proinflammatory T-cell migration and finally is involved in T1D progression, suggesting that inhibition of MET formation may be a potential therapeutic target in T1D.
过量形成的巨噬细胞胞外诱捕网（MET）已被牵涉到几种自身免疫性疾病的发病机制中；然而，其对 1 型糖尿病（T1D）和相关机制的影响仍然是个谜。我们证明了肽基精氨酸脱亚氨酶 4（PAD4）在驱动 NOD 小鼠肠道炎症中大量 MET 形成和巨噬细胞 M1 极化中的关键作用。PAD4 的基因敲除或 MET 的过继转移改变了肠道中促炎 T 细胞的比例，进而影响它们向胰腺的迁移。结合 RNA 测序和 CUT&Tag 分析，我们发现活化的 PAD4 通过转录调控 CXCL10 的表达。本研究全面研究了结肠中过量 PAD4 介导的 MET 形成如何增加肠道炎症的加重和促炎 T 细胞的迁移，最终参与 T1D 的进展，提示抑制 MET 的形成可能是 T1D 的一个潜在治疗靶点。
