Pattern Recognition Scavenger Receptor CD204 Attenuates Toll-like Receptor 4-induced NF-κB Activation by Directly Inhibiting Ubiquitination of Tumor Necrosis Factor (TNF) Receptor-associated Factor 6

Abstract

The collaboration and cross-talk between different classes of innate pattern recognition receptors are crucial for a well coordinated inflammatory response and host defense. Here we report a previously unrecognized role of scavenger receptor A (SRA; also known as CD204) as a signaling regulator in the context of Toll-like receptor 4 (TLR4) activation. We show that SRA/CD204 deficiency leads to greater sensitivity to LPS-induced endotoxic shock. SRA/CD204 down-regulates inflammatory gene expression in dendritic cells by suppressing TLR4-induced activation of the transcription factor NF-B. For the first time, we demonstrate that SRA/CD204 executes its regulatory functions by directly interacting with the TRAF-C domain of TNF receptor-associated factor 6 (TRAF6), resulting in inhibition of TRAF6 dimerization and ubiquitination. The attenuation of NF-B activity by SRA/CD204 is independent of its ligand-binding domain, indicating that the signaling-regulatory feature of SRA/CD204 can be uncoupled from its conventional endocytic functions. Collectively, we have identified the molecular linkage between SRA/CD204 and the TLR4 signaling pathways, and our results reveal a novel mechanism by which a non-TLR pattern recognition receptor restricts TLR4 activation and consequent inflammatory response. The scavenger receptors (SRs)2 constitute a large family of structurally diverse pattern recognition receptors (PRRs) (1). Scavenger receptor A (SRA), also termed CD204, is a prototypic member of the growing SR family. The role of SRA/CD204 in atherosclerosis has been extensively studied because it was the first receptor identified for modified lipoproteins (e.g. oxidized or acetylated low density lipoproteins) that are pertinent to the development of vascular disease (2). As a PRR primarily expressed on myeloid cells, such as dendritic cells (DCs) and macrophages, SRA/CD204 binds not only to altered or modified self macromolecules but also to a wide range of pathogenassociated molecular patterns, including lipopolysaccharide (LPS), bacterial CpG DNA, and double strand RNA (3). SRA/ CD204-deficient mice are significantly more susceptible than their wild type (WT) counterparts to infection with Listeria monocytogenes (2) and Staphyloccus aureus (4). Loss of SRA/ CD204 expression led to an increased mortality in Bacillus Calmette-Guérin primed animals, which has been partially attributed to the overproduction of proinflammatory cytokines by macrophages rather than impaired LPS clearance in vivo (5). Several lines of evidence suggest that SRA/CD204 on myeloid cells functions as a suppressor that can limit an inflammatory response (6, 7). However, the molecular basis underlying the SRA/CD204-mediated regulation of inflammation and production of inflammatory cytokines remains unexplored.The Toll-like receptors (TLRs) represent a family of evolutionarily conserved PRRs and are believed to play central roles in the induction of innate as well as adaptive immunity to pathogen infection (8). Binding of the microbial pattern molecules (i....

Poxviral Protein A52 Stimulates p38 Mitogen-activated Protein Kinase (MAPK) Activation by Causing Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) Self-association Leading to Transforming Growth Factor β-activated Kinase 1 (TAK1) Recruitment

“…Fig. 3A shows that, as reported previously (33), LPS stimulation of cells caused a fraction of TRAF6 within cells to oligomerize, as detected by the appearance of a TRAF6 band of reduced mobility on a native gel (top panel, compare lane 2 to lane 1). This correlated with the activation of p38, as measured by the appearance of phospho-p38 in cell lysates (Fig.…”

Scavenger Receptor-A (CD204): A Two-Edged Sword in Health and Disease

“…43,94–99 In vivo studies have shown that mice lacking SR-A (SR-A −/− ) had a lower survival rate after endotoxin treatment than did their WT counterparts. 94,98,99 This decreased survival was correlated with an increased cytokine response in cultured macrophages and increased pro-inflammatory cytokines in the systemic circulation, in particular, increased levels of TNFα, interleukin 6, and interferon-b 94,98,99 . Yu et al reported that the anti-inflammatory effect of SR-A was due to down-regulation of inflammatory gene expression via decreased TLR4-mediated NFκB activation in dendritic cells.…”

“…Yu et al reported that the anti-inflammatory effect of SR-A was due to down-regulation of inflammatory gene expression via decreased TLR4-mediated NFκB activation in dendritic cells. 99 Haworth et al reported the direct involvement of TNFα in the increased susceptibility of mice lacking SR-A after endotoxemia. 94 In contrast to the studies listed above, Kobyashi et al reported that the presence of SR-A was detrimental to mice after LPS treatment.…”

Scavenger receptor SRA attenuates microglia activation and protects neuroinflammatory injury in intracerebral hemorrhage

“…Scavenger receptor SRA is expressed primarily on myeloid cells, including DCs, and functions as an innate pattern recognition receptor (Ozment et al, 2012;Yu et al, 2011;Seimon et al, 2006). In addition to the established roles that SRA plays in lipid metabolism, atherosclerosis and pathogen recognition, the evidence also demonstrates that SRA serves as a suppressor of vaccine-induced antitumor immunity Qian et al, 2011;Guo et al, 2012).…”