IL-33-ST2 axis regulates myeloid cell differentiation and activation enabling effective club cell regeneration

Abstract

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.

A crosstalk between type 2 innate lymphoid cells and alternative macrophages in lung development and lung diseases (Review)

“…Thus, it is hypothesized that IL-33 promotes proliferation and activation of ILC2s and M2 macrophages during lung development, and crosstalk between ILC2s and M2 macrophages promotes alveolarization. This is consistent with the IL-33-ST2 axis regulating regeneration of epithelial through activation of monocyte differentiation into reparative M2 macrophages and ILC2s-mediated M2 macrophages ( 95 ). In summary, ILC2s promote the polarization of M2 macrophages via IL-4/13.…”

Maintenance of Barrier Tissue Integrity by Unconventional Lymphocytes

“…ILC2 react quickly to injury-induced IL-33 by producing IL-13 and IL-5 (16,20) (Figures 1-3). There is variability in the responses at different tissue sites and skin ILC2 display FIGURE 3 | Proposed mechanisms by which unconventional lymphocytes promote lung repair.…”

“…ILC2 were identified as the primary producers of IL-13 in this model and their presence was required for AAM development and recruitment of ST2 + macrophages. The absence of ILC resulted in a defect in regeneration that was rescued by ILC2 transfer (20). In addition, these ILC2 also produced GM-CSF which plays a key role in macrophage development (20).…”

“…The absence of ILC resulted in a defect in regeneration that was rescued by ILC2 transfer (20). In addition, these ILC2 also produced GM-CSF which plays a key role in macrophage development (20). It is likely that the influence of ILC2 on myeloid cells, in particular macrophages but potentially also eosinophils (via IL-5), is important for repair (Figures 2 and 3), especially as ILC2 are a major, innate source of IL-13 which can be produced more rapidly than adaptive sources, particularly in sterile injury.…”

Airway-Associated Macrophages in Homeostasis and Repair

“…Previous studies have shown that these myeloid cells increase in number after epithelial injury ( Tadokoro et al, 2014 ), and Th2 cytokines influence the cellular composition of the airway epithelium ( Danahay et al, 2015 ; Kuperman et al, 2002 ). Recent data implicate alternatively activated macrophages as critical components of the regenerative niche after injury of the airway epithelium ( Dagher et al, 2020 ).…”