Heme induces inflammatory injury by directly binding to the complex of myeloid differentiation protein 2 and toll-like receptor 4.

Abstract

Heme, as an essential component of hemoproteins, is a prosthetic co-factor found in many cells, which is essential for physiologically vital oxygen transport. However, extracellular or circulatory heme is cytotoxic and triggers inflammation. Although the proinflammatory role of heme has been reported to be associated with Toll-like receptor 4 (TLR4) signaling, the exact mechanism remains unknown. Here, we show that heme promotes TLR4 signaling and inflammation via directly physically interacting with TLR4 and its adaptor protein myeloid differentiation protein 2 (MD2). Genetic loss of MD2 ameliorates heme-induced inflammation and inflammatory cytokine production in the spleen of MD2 knockout (MD2-/-) mice. Using mouse macrophage RAW 264.7 cell line, we show that heme induces TLR4 dimerization and MD2/TLR4/MyD88 activation by physically interacting with TLR4 and MD2 in vitro. Genetic loss of MD2 inhibits heme-induced inflammation and MAPK/NF-κB pathway in mouse primary macrophages extracted from MD2-/- mice. Furthermore, pharmacological inhibition of MD2 by L6H9 ameliorates heme-induced inflammation in macrophages. These findings demonstrate that heme causes inflammation by directly binding to MD2/TLR4 complex, leading to activation of TLR4/MAPK/NF-κB signaling pathway and production of downstream effectors of inflammation.

• Authors: Jianjun Lin, Ke Lin, Lijiang Huang, Yongsheng Jiang, Xiaoxiao Ding, Wu Luo, Aleksandr V Samorodov, Valentin N Pavlov, Guang Liang, Jianchang Qian, Yi Wang
• Journal: Toxicology letters (Toxicol Lett) Vol. 370 Pg. 15-23 (Nov 01 2022) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 36115635 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Cytokines
• Lipopolysaccharides
• Ly96 protein, mouse
• Lymphocyte Antigen 96
• Myeloid Differentiation Factor 88
• NF-kappa B
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Heme
• Oxygen

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Cytokines (metabolism)
• Heme (metabolism)
• Inflammation (chemically induced)
• Lipopolysaccharides (pharmacology)
• Lymphocyte Antigen 96 (metabolism)
• Mice
• Mice, Inbred C57BL
• Myeloid Differentiation Factor 88 (genetics, metabolism)
• NF-kappa B (metabolism)
• Oxygen
• Toll-Like Receptor 4 (genetics, metabolism)