Class B Scavenger Receptor CD36 as a Potential Therapeutic Target in Inflammation Induced by Danger-Associated Molecular Patterns
Irina N. Baranova,
Alexander V. Bocharov,
Tatyana G. Vishnyakova,
Zhigang Chen,
Yunbo Ke,
Anna A. Birukova,
Peter S. T. Yuen,
Takayuki Tsuji,
Robert A. Star,
Konstantin G. Birukov,
Amy P. Patterson,
Thomas L. Eggerman
Affiliations
Irina N. Baranova
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
Alexander V. Bocharov
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
Tatyana G. Vishnyakova
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
Zhigang Chen
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
Yunbo Ke
Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Anna A. Birukova
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Peter S. T. Yuen
Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Takayuki Tsuji
Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Robert A. Star
Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Konstantin G. Birukov
Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Amy P. Patterson
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
Thomas L. Eggerman
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
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.
