Arachidonic acid inhibits inflammatory responses by binding to myeloid differentiation factor-2 (MD2) and preventing MD2/toll-like receptor 4 signaling activation

Publication date: Available online 14 January 2020Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): Yali Zhang, Hongjin Chen, Wenxin Zhang, Yan Cai, Peiren Shan, Di Wu, Bing Zhang, Hui Liu, Khan Zia, Guang LiangAbstractArachidonic acid (AA) plays a fundamental role in the function of all cells. Metabolites of AA contribute to inflammation as well as for resolving inflammation. Although AA-derived metabolites exhibit well-substantiated bioactivity, it is not known whether AA regulates inflammatory responses independent of its metabolites. With the recent discovery that saturated fatty acids activate toll-like receptor-4 (TLR4), we tested the hypothesis that AA directly regulates inflammatory responses through modulating the activity of TLR4. In cultured cardiomyocytes and macrophages, we found that AA prevents saturated fatty acid-induced TLR4 complex formation with accessory proteins and the induction of proinflammatory cytokines. We discovered that AA directly binds to TLR4 co-receptor, myeloid differentiation factor 2 (MD2) and prevents saturated fatty acids from activating TLR4 pro-inflammatory signaling pathway. Similarly, AA reduced lipopolysaccharide (LPS)-induced inflammation in macrophages and septic death in mice through binding to MD2. In high-fat diet mouse model of obesity and LPS-induced model of acute lung injury, both mediating inflammatory responses through TLR4, treatment with AA prevented MD2/TLR4 dimerization, induction of i...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research