SR-A/MARCO–mediated ligand delivery enhances intracellular TLR and NLR function, but ligand scavenging from cell surface limits TLR4 response to pathogens

Abstract

Phagocytic and pathogen sensing receptors are responsible for particle uptake and inflammation. It is unclear how these receptors' systems influence each other's function to shape an innate response. The class-A scavenger receptors SR-A (scavenger receptor A) and MARCO (macrophage receptor with collagenous structure) are 2 well-characterized phagocytic receptors that are unable to initiate inflammatory responses by themselves, yet are implicated in the pathogenesis of various inflammatory disorders. However, the mechanism for such an apparent discrepancy is still unclear. We utilized SR-A IntroductionInnate immune recognition of microbes by pattern recognition receptors (PRRs) initiates 2 distinct effector responses, phagocytosis and inflammation, to promote pathogen clearance, killing, tissue repair, and induction of adaptive immunity. 1 Phagocytic PRRs, such as scavenger receptors, and pathogen sensors, such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs), mediate uptake and initiate inflammation, respectively. 2,3 Although much has been learned about these 2 processes separately, knowledge is still limited on how these processes are coordinated during the host response. Functional collaboration between innate receptor families must exist to coordinate uptake and inflammation; breakdown in such receptor collaboration can lead to defective pathogen clearance and inflammatory pathologies. 4 The scavenger receptor A (SR-A) and macrophage receptor with collagenous structure (MARCO) are 2 well-characterized, nonopsonic phagocytic receptors on myeloid cells. 5,6 Due to their shared multidomain structure and their ability to bind modified low-density lipoprotein and other polyanionic ligands (a common feature of all scavenger receptors), they are defined as members of the class-A scavenger receptor family. Both molecules are multiligand, multifunctional receptors 7 ; share large numbers of overlapping but distinct polyanionic ligands; and carry out common functions such as cellular adhesion, 8 migration, 9 phagocytosis, and antigen presentation. 10 Both receptors have been shown to bind a range of isolated microbial components 11-14 and intact Grampositive and Gram-negative organisms, 15,16 and their nonredundant role in host defense has been established in a variety of bacterial infection models. [17][18][19][20] Although SR-A and MARCO recognize a range of highly inflammatory ligands, these receptors by themselves are unable to initiate inflammatory signaling, which is usually triggered by sensing PRRs that share overlapping ligand repertoires. However, SR-A and MARCO have been implicated in the pathogenesis of a range of chronic and acute inflammatory pathologies, including atherosclerosis, Alzheimer disease, granuloma formation, and septic shock. 21 Studies utilizing both microbial and sterile inflammatory stimuli and distinct models of inflammation have suggested both proinflammatory and anti-inflammatory roles; however, the mechanisms for such apparent discrepancies are unknown. Therefore, how SR-A...

Cutting Edge: Marginal Zone Macrophages Regulate Antigen Transport by B Cells to the Follicle in the Spleen via CD21

“…MARCO is known to be upregulated by bacterial Ag (such as LPS) (17) and, thus, was studied in the context of host defense against infections (18). Because it is known to be connected to downstream signals through TLR (19,20) we further assessed the effect of MARCO cross-linking in MyD88-, TLR2-, TLR4-, or TLR9-deficient mice. The data showed similar reductions in CD21 expression levels after anti-MARCO Ab treatment in all mice (Supplemental Fig.…”

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

“…pathogens enter the host cells [14]. Certain SRs can also function as co-receptors, presenting certain ligands to other danger receptors such as TLRs [15][16][17]. As a result, an effector immune response is assembled.…”

Macrophage SR-BI regulates LPS-induced pro-inflammatory signaling in mice and isolated macrophages

“…Possible interaction of TLR4 with SR-BI, shown in the current study to attenuate the infl ammatory response to LPS, remains to be determined. In contrast to CD36, scavenger receptor A can attenuate TLR4-induced pro-infl ammatory cytokine production by mediating rapid internalization and clearance of extracellular LPS, thus reducing LPS-induced TLR4 activation and infl ammatory signaling ( 31 ). In the current study, LPS binding and cell association was not altered in SR-BI-null macrophages, suggesting that SR-BI does not modify TLR4 activation by affecting LPS clearance.…”