The adhesion GPCR BAI1 mediates macrophage ROS production and microbicidal activity against Gram-negative bacteria

Abstract

The detection of microbes and initiation of an innate immune response occur through pattern recognition receptors (PRRs), which are critical for the production of inflammatory cytokines and activation of the cellular microbicidal machinery. In particular, the production of reactive oxygen species (ROS) by the NADPH oxidase complex is a critical component of the macrophage bactericidal machinery. We previously characterized brain-specific angiogenesis inhibitor 1 (BAI1), a member of the adhesion family of G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors (GPCRs), as a PRR that mediates the selective phagocytic uptake of Gram-negative bacteria by macrophages. We showed that BAI1 promoted phagosomal ROS production through activation of the Rho family guanosine triphosphatase (GTPase) Rac1, thereby stimulating NADPH oxidase activity. Primary BAI1-deficient macrophages exhibited attenuated Rac GTPase activity and reduced ROS production in response to several Gram-negative bacteria, resulting in impaired microbicidal activity. Furthermore, in a peritoneal infection model, BAI1-deficient mice exhibited increased susceptibility to death by bacterial challenge because of impaired bacterial clearance. Together, these findings suggest that BAI1 mediates the clearance of Gram-negative bacteria by stimulating both phagocytosis and NADPH oxidase activation, thereby coupling bacterial detection to the cellular microbicidal machinery.

EhRho1 regulates phagocytosis by modulating actin dynamics through EhFormin1 and EhProfilin1 inEntamoeba histolytica

“…Among the identified proteins, EhRho1 has been selected for this study. Recent studies have shown that GPCRs can sense bacterial chemo attractants and help to direct Dictyostelium discoideum cells towards bacterial engulfment (Billings et al, 2016;Senoo, Sesaki, & Iijima, 2016). EhRho1 is expected to work as downstream signalling molecule in the GPCR-bound heterotrimeric G protein pathway (Bosch & Siderovski, 2013).…”

BAI1 Orchestrates Macrophage Inflammatory Response to HSV Infection—Implications for Oncolytic Viral Therapy

“…BAI1 is known to function as a phagocytic receptor, which contributes to engulfment and clearance of apoptotic cells (14) and Gram-negative bacteria (18, 40). As an engulfment receptor, it functions via recognition and binding to phosphatidyl serine on apoptotic cells and to cell surface LPS of Gram-negative bacteria of infected cells (14, 16, 41) via its thrombospondin type 1 repeats (TSRs), triggering Rac1 activation of ELMO/Doc, resulting in increased phagocytic activity (18).…”

“…As an engulfment receptor, it functions via recognition and binding to phosphatidyl serine on apoptotic cells and to cell surface LPS of Gram-negative bacteria of infected cells (14, 16, 41) via its thrombospondin type 1 repeats (TSRs), triggering Rac1 activation of ELMO/Doc, resulting in increased phagocytic activity (18). Bai1 knockout mice exhibit impaired anti-microbial activity, and increased susceptibility to bacterial sepsis (40). Here our results show for the first time that, while wildtype primary bone marrow derived macrophages inhibited oHSV replication in co-cultured glioma cells, Bai1 −/− macrophages were defective in their ability to curb virus replication, implicating an antiviral role for this multifunctional cell surface receptor.…”

Early innate immune responses to bacterial LPS

“…CD14 endocytosis therefore revealed the first innate immune response to LPS that does not depend on TLR4. This discovery set the stage for the identification of other TLR4-independent responses to LPS, such as the activation of ROS production by BAI1 [14] and the assembly of non-canonical inflammasomes by caspase-11 (caspase4/5 in humans) [15–17]. …”