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. 2020 Mar 20;11:484. doi: 10.3389/fimmu.2020.00484

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Copyright © 2020 Yang, Wang and Andersson.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Inhibiting TLR4- or RAGE-mediated effects induced by HMGB1 or LPS-HMGB1 complexes. During endotoxemia, LPS and extracellular HMGB1 forms complexes that are endocytosed via the RAGE-dependent pathway. LPS and HMGB1 activate TLR4 system. The unique contribution by HMGB1 is disruption of the lysosomal membrane enabling LPS to reach and activate its cytosolic receptor caspase-11, which cleaves gasdermin D to form an active oligomer. Activated gasdermin D will subsequently start coagulation and cause cellular pyroptosis in murine macrophages. The HMGB1-specific inhibitors recombinant HMGB1 box A, anti-HMGB1 m2G7, and acetylcholine each inhibits the cellular internalization of LPS-HMGB1 complexes and resultant immune activation. Anti-HMGB1 m2G7 and acetylcholine also inhibit HMGB1/TLR4-mediated inflammation, whereas P5779 and resveratrol selectively block the HMGB1/TLR4 pathway only.