HMGB1-TLR4-IL-23-IL-17A axis accelerates renal ischemia-reperfusion injury via the recruitment and migration of neutrophils.

Renal ischemia-reperfusion injury (IRI) is an important cause of setting off acute kidney injury. Neutrophil-mediated immunomodulation has a pivotal role in the evolving of IRI. The HMGB1-TLR4-IL-23-IL-17A axis gives rise to neutrophil activation. Therefore, in the study, the role of the HMGB1-TLR4-IL-23-IL-17A axis in IRI was evaluated. Cell viability, inflammation, apoptosis, oxidative stress, survival, renal function and pathology, and the activation of macrophages and neutrophils were measured. Moreover, we evaluated the acetylation, translocation, and secretion of HMGB1 as well as levels of TLR-4, IL-23, IL-17A, and neutrophil chemokines (KC, LIX, and MIP-2). In vivo, anti-HMGB1 antibody decreased the acetylation, translocation, and secretion of HMGB1, reduced the expression of TLR-4, IL-23, IL-17A, KC, LIX, and MIP-2, alleviated the activation of macrophages and neutrophils, improved the survival rate and renal dysfunction, and decreased inflammation, apoptosis, oxidative stress, and pathological injury of the kidney. However, the intervention with recombinant HMGB1(R-HMGB1) significantly abolish the above effect of anti-HMGB1 in IRI. Neutralization IL-23 or IL-17A can alleviated the neutrophils mediated renal dysfunction by suppressing inflammation, apoptosis, and oxidative stress in IRI. In vitro, we confirmed that hypoxic/deoxygenation (H/R) induces the secretion of HMGB1 though acetylation on HK-2 and HMGB1 promotes the secretion of IL-23 in a HMGB1/TLR-4-dependent manner on macrophages. Together, these results implied that the HMGB1-TLR4-IL-23-IL-17A axis regulates inflammation, oxidative stress, apoptosis, and renal injury in IRI by promoting the recruitment and migration of neutrophils.