Abstract
Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in innate and adaptive immune responses. IL-33 triggers pleiotropic immune functions in multiple types of immune cells, which express the IL-33 receptor, ST2. Recent studies have revealed the potential applications of IL-33 for treating acute kidney injury in preclinical animal models. However, IL-33 and IL-33-responding immune cells are reported to exhibit both detrimental and beneficial roles. The IL-33-mediated immunomodulatory functions have been investigated using loss-of-function approaches, such as IL33-deficient mice, IL-33 antagonists, or administration of exogenous IL-33 recombinant protein. This review will discuss the key findings on IL-33-mediated activation of kidney resident group 2 innate lymphoid cells (ILC2s) and summarize the current understanding of the differential functions of endogenous IL-33 and exogenous IL-33 and their potential implications in treating acute kidney injury.
Highlights
Interleukin (IL)-33, a nuclear cytokine belonging to the IL-1 family, has pleiotropic immunomodulatory functions and is involved in various inflammatory diseases [1]
The analyses revealed that the kidney ILC2s exhibited lower CD25 expression, consistent expression of inducible T cell costimulator (ICOS) and killer cell lectin like receptor G1 (KLRG1), and upregulated IL-5 expression when compared with the lung ILC2s [59]
Endogenous IL-33 Capillary CD31+ endothelial cells are the source of IL-33 IL-33 knockout is protective to ischemia-reperfusion injury (IRI) Reduced myeloid cell infiltration in IL-33 knockout mice Impaired invariant natural killer T-cell (iNKT) recruitment and function in the IL-33 knockout mice Early IL-33 release (1–6 h post injury) is not necessary for myeloid recruitment after IRI IL-33-mediated iNKT activation contributes to neutrophil recruitment during the amplification phase of kidney injury
Summary
Interleukin (IL)-33, a nuclear cytokine belonging to the IL-1 family, has pleiotropic immunomodulatory functions and is involved in various inflammatory diseases [1]. The most common mouse models of AKI that have been generated include ischemia-reperfusion injury (IRI), chemical-induced injury (doxorubicin or cisplatin), and UUO [40,41,42] These animal models have helped improve our understanding of tissue responses to acute kidney insults and the involvement of different types of immune cells or cytokines in the inflammatory and reparative phases [35]. Recent studies have demonstrated that IL-33-mediated immune responses are involved in renal protection using mouse AKI models [48,49,50,51] The growth factors, such as amphiregulin (AREG) derived from IL-33-responsive group 2 innate lymphoid cells (ILC2s) or Tregs, are reported to promote epithelium regeneration after tissue injury [52]. This review summarizes the current findings on IL-33-mediated immune responses in kidney injury, repair, and fibrosis
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