Inserm UMR1152-Physiopathologie et Epidémiologie des Maladies Respiratoires, Université Paris, Paris, France.
Faculté de Médecine, Université Paris, Paris, France.
Nat Commun. 2020 Sep 22;11(1):4786. doi: 10.1038/s41467-020-18466-w.
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.
证据表明巨噬细胞在组织再生中具有不可或缺的功能，但潜在的分子机制仍不清楚。在这里，我们证明了 IL-33-ST2 轴在支气管上皮修复中的保护作用，并暗示 ST2 参与了髓样细胞分化。在小鼠中缺乏 ST2 会导致肺髓样细胞浸润减少、异常的选择性激活的巨噬细胞（AAM）功能以及萘诱导损伤后上皮修复受损。将野生型（WT）AAMs 重建到 ST2 缺陷型小鼠中可完全恢复支气管再上皮化。这一机制的核心是 IL-33-ST2 信号对单核细胞/巨噬细胞分化、自我更新和修复能力的直接影响，这表现在 ST2 小鼠中调节髓样细胞周期、成熟和上皮龛再生功能的关键途径下调。因此，IL-33-ST2 轴通过激活包括单核细胞分化为有能力修复的 AAM 以及 2 型先天淋巴样细胞（ILC2）介导的 AAM 激活的大型多细胞回路来控制上皮龛的再生。
