Endogenous IL-33 Contributes to Kidney Ischemia-Reperfusion Injury as an Alarmin

Abstract

Inflammation is a prominent feature of ischemia-reperfusion injury (IRI), which is characterized by leukocyte infiltration and renal tubular injury. However, signals that initiate these events remain poorly understood. We examined the role of the nuclear alarmin IL-33 in tissue injury and innate immune response triggered by experimental kidney ischemia-reperfusion. In wild-type mice, we found that IL-33 was constitutively expressed throughout the kidney in peritubular and periglomerular spaces, mainly by microvascular endothelial cells, from which it was released immediately during IRI. Compared with wild-type mice, mice lacking IL-33 (IL-33) exhibited reductions in early tubular cell injury and subsequent renal infiltration of IFN-/IL-17A-producing neutrophils, with preservation of renal functions. This protection associated with decreased renal recruitment of myeloid dendritic cells, natural killer (NK) cells, and invariant natural killer T (iNKT) cells, the latter of which were reported as deleterious in IRI. Increases in the level of circulating IL-12, a key IL-33 cofactor, and the expression of ST2, an IL-33-specific receptor, on the surface of iNKT cells preceded the IL-33- and iNKT cell-dependent phase of neutrophil infiltration. Furthermore, IL-33 directly targeted iNKT cells , inducing IFN- and IL-17A production. We propose that endogenous IL-33 is released as an alarmin and contributes to kidney IRI by promoting iNKT cell recruitment and cytokine production, resulting in neutrophil infiltration and activation at the injury site. Our findings show a novel molecular mediator contributing to innate immune cell recruitment induced by renal ischemia-reperfusion and may provide therapeutic insights into AKI associated with renal transplantation.

Emerging therapeutic potential of group 2 innate lymphoid cells in acute kidney injury

“…Consistent results were achieved using IL‐33 and soluble ST2 within an IRI model, and a similar conclusion was reached using unilateral ureter obstruction . Mice deficient in either IL‐33 or ST2 ( Il33 −/− or Il1rl1 −/− ) were partially protected against the remodeling and fibrotic changes following injury, and Il33 −/− mice were also protected against features of injury following IRI .…”

“…reached using unilateral ureter obstruction [88,89]. Mice deficient in either IL-33 or ST2 (Il33 −/− or Il1rl1 −/− ) were partially protected against the remodeling and fibrotic changes following injury, and Il33 −/− mice were also protected against features of injury following IRI [89,90]. The dosage of IL-33, length of administration and/or the type of renal injury may drastically alter the response exhibited to be advantageous or deleterious.…”

Emerging Roles of Interleukin-33-responsive Kidney Group 2 Innate Lymphoid Cells in Acute Kidney Injury

“…Genetically modified mice lacking endogenous IL-33 or its receptor (ST2) have been used for the loss-of-function study to examine the role of IL-33/ST2 signaling in the pathogenesis of AKI. Ferhat et al demonstrated that endogenous IL-33 contributes to the recruitment of myeloid cells upon acute IRI using IL33-deficient mice [62]. IL-33 is constitutively expressed on blood vessels, especially peritubular and periglomerular endothelial cells [20,62,68].…”

“…Ferhat et al demonstrated that endogenous IL-33 contributes to the recruitment of myeloid cells upon acute IRI using IL33-deficient mice [62]. IL-33 is constitutively expressed on blood vessels, especially peritubular and periglomerular endothelial cells [20,62,68]. Ferhat et al also demonstrated that endogenous IL-33 is not required for early recruitment of myeloid cells post-IRI (1-6 h) but is required for the amplification of neutrophil-mediated inflammatory response via invariant natural killer T-cell (iNKT) [62].…”

“…IL-33 is constitutively expressed on blood vessels, especially peritubular and periglomerular endothelial cells [20,62,68]. Ferhat et al also demonstrated that endogenous IL-33 is not required for early recruitment of myeloid cells post-IRI (1-6 h) but is required for the amplification of neutrophil-mediated inflammatory response via invariant natural killer T-cell (iNKT) [62]. Based on these results, Ferhat et al concluded that endogenous IL-33 functions as a tissue alarmin and contributes to kidney IRI via IL-33-mediated iNKT activation and enhances neutrophil recruitment following AKI [62].…”