Inhibition of IL-18 reduces renal fibrosis after ischemia-reperfusion.

Acute kidney injury induced by ischemia-reperfusion injury (IRI) is a high risk factor in the progression towards chronic kidney disease, which is featured by renal interstitial fibrosis. Interleukin (IL)-18 is produced by T cells and macrophages and has been involved in the pathophysiology of IRI. However, the role of IL-18 in IRI-induced renal fibrosis is poorly understood. In the present study, we showed that interleukin (IL)-18 was significantly up-regulated after IRI stress. Mice treated with IL-18 Bp, a natural inhibitor of IL-18, presented less severe fibrotic response in the kidneys following IRI compared with vehicle-treated mice. Inhibition of IL-18 decreased myofibroblasts formation in the kidneys in response to IRI, which was associated with reduction of fibronectin and collagenⅠproteins. Moreover, inhibition of IL-18 impaired infiltration of CD3+ T cells and F4/80+ macrophages in the kidneys of mice after IRI. Treatment with IL-18 Bp reduces the levels of profibrotic molecules in the kidneys of mice following IRI. Finally, administration of IL-18 Bp impedes the transition of M2 macrophages to myofibroblasts and suppressed the accumulation of bone marrow-derived M2 macrophages. Adoptive transfer of M2 macrophages abolished the anti-fibrotic effect of IL-18 Bp. In summary, our results suggest that IL-18 plays an important role in the progression of IRI-induced renal fibrosis via modulating inflammation cells infiltration, the expression of inflammatory cytokines and chemokines, and the transition of bone marrow-derived M2 macrophages to myofibroblasts.