Brain angiogenesis inhibitor 1 (BAI1) is a pattern recognition receptor that mediates macrophage binding and engulfment of Gram-negative bacteria

Abstract

Bacterial recognition by host cells is essential for initiation of infection and the host response. Bacteria interact with host cells via multiple pattern recognition receptors that recognize microbial products or pathogen-associated molecular patterns. In response to this interaction, host cell signaling cascades are activated that lead to inflammatory responses and/or phagocytic clearance of attached bacteria. Brain angiogenesis inhibitor 1 (BAI1) is a receptor that recognizes apoptotic cells through its conserved type I thrombospondin repeats and triggers their engulfment through an ELMO1/Dock/Rac1 signaling module. Because thrombospondin repeats in other proteins have been shown to bind bacterial surface components, we hypothesized that BAI1 may also mediate the recognition and clearance of pathogenic bacteria. We found that preincubation of bacteria with recombinant soluble BAI1 ectodomain or knockdown of endogenous BAI1 in primary macrophages significantly reduced binding and internalization of the Gram-negative pathogen Salmonella typhimurium. Conversely, overexpression of BAI1 enhanced attachment and engulfment of Salmonella in macrophages and in heterologous nonphagocytic cells. Bacterial uptake is triggered by the BAI1-mediated activation of Rac through an ELMO/Dock-dependent mechanism, and inhibition of the BAI1/ELMO1 interaction prevents both Rac activation and bacterial uptake. Moreover, inhibition of ELMO1 or Rac function significantly impairs the proinflammatory response to infection. Finally, we show that BAI1 interacts with a variety of Gramnegative, but not Gram-positive, bacteria through recognition of their surface lipopolysaccharide. Together these findings identify BAI1 as a pattern recognition receptor that mediates nonopsonic phagocytosis of Gram-negative bacteria by macrophages and directly affects the host response to infection.innate immunity | lipopolysaccharide-binding | TNF-α

Distinct roles for BAI1 and TIM-4 in the engulfment of dying neurons by microglia

“…5g; . BAI1 has also been implicated in bacterial engulfment 23 and indeed there is a decrease in clearance efficiency when we inject fluorescently labelled bacteria in BAI1 morphant brains ( Supplementary Fig. 2g).…”

Shear Stress–Dependent Downregulation of the Adhesion-G Protein–Coupled Receptor CD97 on Circulating Leukocytes upon Contact with Its Ligand CD55

“…CD55 interacts with the N-terminal epidermal growth factor (EGF)-like domains of CD97 (6)(7)(8), an aGPCR broadly expressed by hematopoietic and nonhematopoietic cells (9)(10)(11). Subsequently identified aGPCR ligands were dermatan sulfate, a5b1 integrin, tissue transglutaminase 2, phosphatidylserine, LPS, C1q, lasso/teneurin-2, collagen III, and Thy-1/CD90 (12)(13)(14)(15)(16)(17)(18)(19)(20). Evidence was obtained that aGPCRs have a role in cell positioning and tissue organization in various organ systems (21,22); however, in the strictest sense, aGPCRs are still functional orphans.…”

Activation of Myeloid Cell-Specific Adhesion Class G Protein-Coupled Receptor EMR2 via Ligation-Induced Translocation and Interaction of Receptor Subunits in Lipid Raft Microdomains

“…Adhesion-GPCRs are thus thought to possess a dual cellular adhesion and signaling function. Recent studies have revealed many important functions for adhesion-GPCRs: these include development of the brain frontal cortex (34), circulation of cerebrospinal fluid (44), central nervous system (CNS)-restricted angiogenesis and vascularization (1, 10, 21), myelination of Schwann cells (30, 31), Usher syndrome (29, 49), cellular polarity (16, 23), epididymal fluid regulation and male fertility (4, 12), and immune recognition and regulation (11,18,27,47), as well as tumor growth and metastasis (8,17,43,50). However, the molecular mechanisms mediating the biological functions of adhesion-GPCRs remain to be fully characterized.…”