Evidence points to an indispensable function of macrophages in tissue regeneration, yet the underlying molecular mechanisms remain elusive. Here we demonstrate a protective function for the IL-33-ST2 axis in bronchial epithelial repair, and implicate ST2 in myeloid cell differentiation. ST2 deficiency in mice leads to reduced lung myeloid cell infiltration, abnormal alternatively activated macrophage (AAM) function, and impaired epithelial repair post naphthalene-induced injury. Reconstitution of wild type (WT) AAMs to ST2-deficient mice completely restores bronchial re-epithelialization. Central to this mechanism is the direct effect of IL-33-ST2 signaling on monocyte/macrophage differentiation, self-renewal and repairing ability, as evidenced by the downregulation of key pathways regulating myeloid cell cycle, maturation and regenerative function of the epithelial niche in ST2^−/− mice. Thus, the IL-33-ST2 axis controls epithelial niche regeneration by activating a large multi-cellular circuit, including monocyte differentiation into competent repairing AAMs, as well as group-2 innate lymphoid cell (ILC2)-mediated AAM activation.

有证据表明巨噬细胞在组织再生中起着不可或缺的作用，但潜在的分子机制仍然难以捉摸。在这里，我们证明了 IL-33-ST2 轴在支气管上皮修复中的保护功能，并暗示 ST2 参与骨髓细胞分化。小鼠 ST2 缺乏导致肺髓细胞浸润减少、替代激活巨噬细胞 (AAM) 功能异常，以及萘诱导损伤后上皮修复受损。将野生型 (WT) AAM 重建为 ST2 缺陷型小鼠可完全恢复支气管上皮再形成。该机制的核心是 IL-33-ST2 信号传导对单核细胞/巨噬细胞分化、自我更新和修复能力的直接影响，正如调节髓细胞周期的关键途径的下调所证明的那样，^-/-小鼠。因此，IL-33-ST2 轴通过激活大型多细胞回路来控制上皮生态位再生，包括单核细胞分化为有能力的修复 AAM，以及第 2 组先天淋巴细胞 (ILC2) 介导的 AAM 激活。