Class B Scavenger Receptor CD36 as a Potential Therapeutic Target in Inflammation Induced by Danger-Associated Molecular Patterns

• Published in: Cells (Basel, Switzerland) Switzerland), 2024-12, Vol.13 (23), p.1992
• Main Authors: Baranova, Irina N, Bocharov, Alexander V, Vishnyakova, Tatyana G, Chen, Zhigang, Ke, Yunbo, Birukova, Anna A, Yuen, Peter S T, Tsuji, Takayuki, Star, Robert A, Birukov, Konstantin G, Patterson, Amy P, Eggerman, Thomas L
• Format: Article
• Language: English
• Subjects: Alarmins - metabolism; Animals; B cells; Bone marrow; CD36; CD36 antigen; CD36 Antigens - metabolism; Chromosomal proteins; DAMPs; Health aspects; Heat shock proteins; HEK293 Cells; Hepatocytes; Histone H3; Histones; HMGB1; HMGB1 protein; Humans; Immune response; Immunity (Disease); Inflammation; Inflammation - metabolism; Inflammation - pathology; Injuries; Innate immunity; Interleukin 6; Kinases; Laboratory animals; Ligands; Lysates; Macrophages; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Musculoskeletal system; Pathogens; Pattern recognition receptors; Peptides; Phosphatase; SAA; Scavenger receptors; Skeletal muscle; Therapeutic targets; Trauma; Tumor necrosis factor-α
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells13231992

The class B scavenger receptor CD36 is known to bind and mediate the transport of lipid-related ligands and it functions as a pattern recognition receptor (PRR) for a variety of pathogens, including bacteria and viruses. In this study, we assessed CD36's role as a PRR mediating pro-inflammatory effects of several known Danger-Associated Molecular Patterns (DAMPs) used either as a single preparation or as a combination of DAMPs in the form of total cell/skeletal muscle tissue lysates. Our data demonstrated that multiple DAMPs, including HMGB1, HSPs, histone H3, SAA, and oxPAPC, as well as cell/tissue lysate preparations, induced substantially higher (~7-10-fold) IL-8 cytokine responses in HEK293 cells overexpressing CD36 compared to control WT cells. At the same time, DAMP-induced secretion of IL-6 in bone marrow-derived macrophages (BMDM) from CD36-/- mice was markedly (~2-3 times) reduced, as compared to macrophages from normal mice. Synthetic amphipathic helical peptides (SAHPs), known CD36 ligands, efficiently blocked CD36-dependent inflammatory responses induced by both cell and tissue lysates, HMGB1 and histone H3 in CD36+ cells. IP injection of total cellular lysate preparation induced inflammatory responses that were assessed by the expression of liver and lung pro-inflammatory markers, including IL-6, TNF-α, CD68, and CXCL1, and was reduced by ~50% in CD36-deficient mice compared to normal mice. Our findings demonstrate that CD36 is a PRR contributing to the innate immune response via mediating DAMP-induced inflammatory signaling and highlight the importance of this receptor as a potential therapeutic target in DAMP-associated inflammatory conditions.