High mobility group box 1 (HMGB1), a crucial proinflammatory cytokine, was reported to activate the absent in melanoma 2 (AIM2) inflammasome, which are both essential in acute lung injury (ALI). However, their interaction mechanism has remained elusive. Macrophages are known to express the AIM2 inflammasome and the main receptors [receptor for advanced glycation end products (RAGE), Toll‑like receptor 2/4 (TLR‑2/TLR‑4)] of HMGB1 to transmit intracellular signals. The present study aimed to indicate whether HMGB1 participates in the process of lipopolysaccharides (LPS)‑induced ALI through activating the AIM2 inflammasome in macrophages, as well as inducing polarization of M1 macrophages via TLR2, TLR4 and RAGE/ nuclear factor‑κB (NF‑κB) signaling pathways. In an in vivo mouse model of LPS‑induced ALI, anti‑HMGB1, recombinant (r)HMGB1, LPS from Rhodobacter sphaeroides (LPS‑RS, TLR2/4 antagonist) or FPS‑ZM1 (RAGE antagonist) were administrated. In in vitro studies, bone marrow‑derived macrophages from mice primed with LPS were stimulated with or without anti‑HMGB1, rHMGB1, LPS‑RS, or FPS‑ZM1. The findings revealed that anti‑HMGB1, LPS‑RS and FPS‑ZM1 significantly decreased infiltration of inflammatory cells, wet‑to‑dry ratio, myeloperoxidase activity in the lung, the levels of cytokines, as well as macrophages and neutrophil infiltration in the bronchoalveolar lavage fluid. However, rHMGB1 aggravated the inflammatory response in ALI. Mechanistically, anti‑HMGB1, LPS‑RS and FPS‑ZM1 attenuated activation of TLR2, TLR4, and RAGE/NF‑κB signaling pathways and expression of the AIM2 inflammasome in macrophages. However, rHMGB1 enhanced their expression levels and induced polarization of M1 macrophages. These results indicated that HMGB1 could participate in the pathogenesis of ALI by activating the AIM2 inflammasome in macrophages, as well as inducing polarization of M1 macrophages through TLR2, TLR4 and RAGE/NF‑κB signaling pathways.
Keywords: acute lung injury; high mobility group box 1; polarization of M1 macrophages; absent in melanoma 2 inflammasome; cytokines.