TAK1 governs monocyte-derived macrophage development in acute sterile peritonitis

Monocytes recruited to inflamed tissues differentiate into macrophages, contributing to the resolution of inflammation and tissue repair. However, the mechanisms underlying the development, differentiation, and maturation of these monocyte-derived macrophages (MOMs) remain incompletely understood. Here, we demonstrate that TGFβ-activated kinase 1 (TAK1), a key signaling mediator downstream of various receptors including cytokine receptors and Toll-like receptors, is essential for MOM development. In a zymosan-induced model of acute sterile peritonitis, mice with myeloid-specific deletion of TAK1 exhibited a severe impairment in MOM development within the peritoneal cavity, in contrast to control mice. Blocking death-receptor signaling with neutralizing-antibodies facilitated the recovery of MOM development in these mice, albeit to a limited extent. We identified a transient population of immediate macrophage precursors differentiating from infiltrating monocytes in the peritoneal cavity. Notably, TAK1-deficient macrophage precursors displayed marked susceptibility to cell death, possibly due to a previously unrecognized mechanism distinct from well-characterized cell death pathways. These findings establish TAK1 as a critical regulator of MOM development and uncover a novel survival mechanism in the macrophage precursors during inflammation.