HMGB1 participates in LPS‑induced acute lung injury by�activating the AIM2 inflammasome in macrophages�and inducing polarization of M1 macrophages via TLR2, TLR4, and RAGE/NF‑κB signaling pathways

Abstract

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 inflamematory 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.

Gut microbial bile acid metabolite skews macrophage polarization and contributes to high-fat diet-induced colonic inflammation

“…Based on the previous research, M1 macrophages polarization is commonly accompanied by inflammasome activation, for instance, HMGB1 was reported to participate in the pathogenesis of acute lung injury by inducing M1 macrophages polarization and activating AIM2 inflammasome. 42 IFN-γ treatment, leading to M1 phenotype of macrophages, could subsequently induce mRNA expression and active protein formation of caspase-1, a critical inflammasome component. 43 In addition, NLRP3 inflammasome activation has been suggested to be initiated by Toll-like receptors (TLRs).…”

The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach

“…Excessive levels of environmental TNF-alpha is a well-documented cause of compromised phagocytosis in these immune cells [ 225 , 226 ]. In addition, high levels of HMBG1 may increase the population of M1 polarised macrophages via a mechanism involving TLR-4 and RAGE activation [ 212 , [227] , [228] , [229] ]. This is of importance from the perspective of impaired efferocytosis, as macrophages polarised in such a manner display inhibited phagocytosis compared to their M2 polarised counterparts [ 230 ].…”

HMGB1-Mediated Neuroinflammatory Responses in Brain Injuries: Potential Mechanisms and Therapeutic Opportunities

“…Previous pre-clinical studies have demonstrated that by inhibiting the activation of the M1 phenotype and increasing the activation of the M2 phenotype, the neuronal damage was ameliorated and the functional recovery after TBI was enhanced [ 55 , 56 ], suggesting the modulation of microglia/macrophage polarization as a novel therapeutic strategy. HMGB1 has been shown to activate macrophages via TLR4, TLR2, and RAGE/NF-κB signaling cascades, and induce the polarization of macrophages into M1 phenotype [ 57 ]. In an experimental TBI study, treatment with the natural HMGB1 inhibitor, glycyrrhizin could improve the functional recovery, decrease the lesion volume, suppress the HMGB1 expression and release, as well as reduce the activation of M1 phenotype while promoting the activation of M2 phenotype of microglia/macrophages after TBI [ 58 ].…”