Heme oxygenase-1 ameliorates LPS-induced acute lung injury correlated with downregulation of interleukin-33

Although studies have shown that heme oxygenase-1 (HO-1) can abrogate leukocyte recruitment and tissue injury after LPS stimulation, the underlying mechanisms remain incompletely understood. Interleukin (IL)-33, a new member of the IL-1 family, is found to play a crucial immunoregulatory effect on the MD2/TLR4 complex expression. Moreover, TLR4 further promotes the activation of NF-κB and the production of proinflammatory mediators, which exacerbate neutrophil infiltration and organ damage. The present study was designed to determine whether the protection of HO-1 against LPS-induced acute lung injury (ALI) is involved in downregulation of IL-33. We observed that the levels of IL-33 mRNA and protein in LPS-stimulated macrophages were strongly suppressed by a potent HO-1 inducer, CoPP, treatment. Meanwhile, CoPP significantly reduced the expression of TLR4 and TNF-α in IL-33-pretreated macrophages followed LPS challenge. In the murine model of LPS-induced ALI, CoPP treatment resulted in a remarkable decrease in LPS-mediated leukocyte exudation, Evans blue dye albumin (EBA) leakage as well as histopathologic disruption. Notably, CoPP treatment markedly inhibited the expression of IL-33 and TLR4 in lung tissues under LPS stimulation. Therefore, these data suggest that the cytoprotection of HO-1 in LPS-induced pulmonary injury is associated with negative regulation of IL-33 and TLR4-mediated inflammatory response.

► The protection of HO-1 against LPS-induced ALI is correlated with IL-33. ► IL-33 enhances TLR4 and cytokine response of macrophages to LPS. ► The expression and activity of IL-33 responded to LPS is abrogated by HO-1. ► HO-1 upregulation improves LPS-induced pulmonary damage in mice. ► HO-1 protection is associated with suppression of IL-33/TLR4-mediated inflammation.