ILC2s expanded by exogenous IL-33 regulate CD45+CD11b+F4/80high macrophage polarization to alleviate hepatic ischemia-reperfusion injury

Abstract

Hepatic ischemia-reperfusion injury (IRI) is an adverse consequence of hepatectomy or liver transplantation. Recently, immune mechanisms involved in hepatic IRI have attracted increased attention of investigators working in this area. In specific, group 2 innate lymphoid cells (ILC2s), have been strongly implicated in mediating type 2 inflammation. However, their immune mechanisms as involved with hepatic IRI remain unclear. Here, we reported that the population of ILC2s is increased with the development of hepatic IRI as shown in a mouse model in initial stage. Moreover, M2 type CD45+CD11b+F4/80high macrophages increased and reached maximal levels at 24 h followed by a significant elevation in IL-4 levels. We injected exogenous IL-33 into the tail vein of mice as a mean to stimulate ILC2s production. This stimulation of ILC2s resulted in a protective effect upon hepatic IRI along with an increase in M2 type CD45+CD11b+F4/80high macrophages. In contrast, depletion of ILC2s as achieved with use of an anti-CD90.2 antibody substantially abolished this protective effect of exogenous IL-33 and M2 type CD45+CD11b+F4/80high macrophage polarization in hepatic IRI. Therefore, this exogenous IL-33 induced potentiation of ILC2s appears to regulate the polarization of CD45+CD11b+F4/80high macrophages to alleviate IRI. Such findings provide the foundation for the development of new targets and strategies in the treatment of hepatic IRI.

Type 2 innate lymphoid cells are protective against hepatic ischaemia/reperfusion injury

“…These results are supported by recent work demonstrating that ILC2s appear to regulate the polarisation of macrophages to alleviate hepatic IRI after IL-33 administration. 38 Although this study did not investigate the underlying mechanisms, we have demonstrated a critical role for ILC2–IL-13–macrophage pathways in mediating this protection. Moreover, our work suggests that IL-13 may possess an additional protective role in other cells.…”

“…In response to IRI, numerous studies have indeed described how ILC2s become licensed to protect against injury in various organs through suppressing the onset of immune responses or enhancing tissue regeneration. 18 , 22 , 38 , 44 We recently demonstrated for the first time that the ILC2-activating cytokine IL-25, IL-33, or ex vivo -expanded ILC2s could reduce tubular cell injury and improve kidney function in renal IRI. 18 , 22 In the context of hepatic IRI, and consistent with our results, other groups have shown that ILC2s play a protective role by modulating macrophage polarisation.…”

“… 18 , 22 In the context of hepatic IRI, and consistent with our results, other groups have shown that ILC2s play a protective role by modulating macrophage polarisation. 38 Furthermore, ILC2s demonstrated a direct and protective role in the recovery of experimental myocardial infarction, 44 a condition similar to IRI, via ILC2-derived IL-5 and reparative heart macrophages. Until now, the direct role of ILC2-derived IL-5 and IL-13 (and downstream pathways) was not clear.…”

Responses of hepatic sinusoidal cells to liver ischemia–reperfusion injury

“…Group 2 innate lymphoid cells stimulated with IL-33 alleviate liver IRI through IL-4-mediated macrophage shifting toward a reparative phenotype that expresses CD11 b + F4/80 high CD206 high in mice ( Zhang et al, 2022 ).…”