Vibrio cholerae OmpU Mediates CD36-Dependent Reactive Oxygen Species Generation Triggering an Additional Pathway of MAPK Activation in Macrophages

• Published in: The Journal of immunology (1950) 2019-04, Vol.202 (8), p.2431-2450
• Main Authors: Prasad, G V R Krishna, Dhar, Vinica, Mukhopadhaya, Arunika
• Format: Article
• Language: English
• Subjects: Adhesins, Bacterial - immunology; Animals; CD36 Antigens - immunology; Humans; Macrophages - immunology; Macrophages - pathology; MAP Kinase Signaling System - immunology; Mice; Monocytes - immunology; Monocytes - pathology; RAW 264.7 Cells; Reactive Oxygen Species - immunology; THP-1 Cells; Vibrio cholerae - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1800389

OmpU, one of the porins of Gram-negative bacteria , induces TLR1/2-MyD88-NF-κB-dependent proinflammatory cytokine production by monocytes and macrophages of human and mouse origin. In this study, we report that in both the cell types, OmpU-induced proinflammatory responses involve activation of MAPKs (p38 and JNK). Interestingly, we observed that in OmpU-treated macrophages, p38 activation is TLR2 dependent, but JNK activation happens through a separate pathway involving reactive oxygen species (ROS) generation by NADPH oxidase complex and mitochondrial ROS. Further, we observed that OmpU-mediated mitochondrial ROS generation probably depends on OmpU translocation to mitochondria and NADPH oxidase-mediated ROS production is due to activation of scavenger receptor CD36. For the first time, to our knowledge, we are reporting that a Gram-negative bacterial protein can activate CD36 as a pattern recognition receptor. Additionally, we found that in OmpU-treated monocytes, both JNK and p38 activation is linked to the TLR2 activation only. Therefore, the ability of macrophages to employ multiple receptors such as TLR2 and CD36 to recognize a single ligand, as in this case OmpU, probably explains the very basic nature of macrophages being more proinflammatory than monocytes.