Physical Interactions With Bacteria and Protozoan Parasites Establish the Scavenger Receptor SSC4D as a Broad-Spectrum Pattern Recognition Receptor

Abstract

Since the pioneering discoveries, by the Nobel laureates Jules Hoffmann and Bruce Beutler, that Toll and Toll-like receptors can sense pathogenic microorganisms and initiate, in vertebrates and invertebrates, innate immune responses against microbial infections, many other families of pattern recognition receptors (PRRs) have been described. One of such receptor clusters is composed by, if not all, at least several members of the scavenger receptor cysteine-rich (SRCR) superfamily. Many SRCR proteins are plasma membrane receptors of immune cells; however, a small subset consists of secreted receptors that are therefore in circulation. We here describe the first characterization of biological and functional roles of the circulating human protein SSC4D, one of the least scrutinized members of the family. Within leukocyte populations, SSC4D was found to be expressed by monocytes/macrophages, neutrophils, and B cells, but its production was particularly evident in epithelial cells of several organs and tissues, namely, in the kidney, thyroid, lung, placenta, intestinal tract, and liver. Similar to other SRCR proteins, SSC4D shows the capacity of physically binding to different species of bacteria, and this opsonization can increase the phagocytic capacity of monocytes. Importantly, we have uncovered the capacity of SSC4D of binding to several protozoan parasites, a singular feature seldom described for PRRs in general and here demonstrated for the first time for an SRCR family member. Overall, our study is pioneer in assigning a PRR role to SSC4D.

The liver in sepsis: molecular mechanism of liver failure and their potential for clinical translation

“…The importance of hepatocytes as a non-specialized immune cell with no phagocytic activity for immune control is astonishing. Hepatocytes in the liver serve as bacterial scavengers, detoxifying cells for all xenobiotics, the primary source for APPs, and producing inflammatory cytokines (Protzer et al 2012 ; Cardoso et al 2021 ). All those effects modulate the systemic immune response.…”

Specific interaction between Group BStreptococcusCC17 hypervirulent clone and phagocytes

“…The inhibitory effect of fucoidan and poly(I) on CC17 phagocytosis led us to conclude that scavenger receptor(s) might be involved in the adhesion and/or uptake of non-opsonized CC17 bacteria by macrophages. Interestingly, it has been recently described that the scavenger receptor SSC4D interacts with BM110 (CC17 strain) (47). SSCD4 is a secreted scavenger receptor rendering this molecule unlikely involved in the initial adherence of CC17 bacteria to the macrophage surface.…”

“…Since scavenger receptors have a wide distribution, being expressed by phagocytes as well as by epithelial and endothelial cells (37), it is tempting to speculate that Spb1 and HvgA promote adhesion to host cells by recognizing the same receptors on phagocytes, epithelial and endothelial cells. Interestingly, it has been recently described that the scavenger receptor SSC4D, expressed by phagocytes and epithelial cells, interacts with BM110 strain (50). SSCD4 is a secreted scavenger receptor making this molecule unlikely to be involved in the initial adherence of CC17 bacteria to the macrophage surface.…”

Quantitative proteomics analysis of COVID-19 patients: Fetuin-A and tetranectin as potential modulators of innate immune responses

“…Additionally, innate immune responses are considered the key factors in modulating the progress of the disease towards asymptomatic, mild, moderate, severe or extremely severe clinical phenotypes [ 6 , 7 ]. Neutrophils and monocyte/macrophages are the crucial frontline defense elements driving the innate immune responses during infection [ 8 , 9 ]. SARS-CoV-2 spike protein might activate macrophages directly via the ACE2 receptor present in these cells [ 10 ].…”