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.
Highlights
The initial sensing of an invasive pathogen is one of the most critical events during an infection and is mediated by germlineencoded pattern recognition receptors (PRRs), which identify and bind conserved pathogen-associated molecular patterns (PAMPs) of microbes
A certain separation can be established between the scavenger receptor cysteine-rich (SRCR) group B members that are secreted from those that are membrane bound, such as CD5, CD6, CD163, and CD163 antigen-like 1 (M160), in that in this latter set, N-linked glycosylation seems to be more prevalent, despite that the whole level of sequence similarity between the different proteins would not predict that sort of cleavage [14, 42]
We show for the first time the capacity of SSC4D to physically bind to bacteria and protozoan parasites
Summary
The initial sensing of an invasive pathogen is one of the most critical events during an infection and is mediated by germlineencoded pattern recognition receptors (PRRs), which identify and bind conserved pathogen-associated molecular patterns (PAMPs) of microbes. Membranebound Toll-like receptors (TLRs) or C-type lectin receptors bind or sense microbe-exposed PAMPs and initiate signaling cascades to trigger innate immune cell activation, whereas intracellular pathogens or their by-products are recognized by intracellular PRRs such as cytoplasmic NOD-like receptors or by RIG-I-like receptors and endosomal TLRs that identify microbial genetic material [1,2,3,4]. The macrophage scavenger receptor type I (MSR1) and MARCO plasma membrane trimeric proteins have long been known to bind bacteria or bacterial endotoxins and to promote microbial phagocytosis [5, 6], but only more recently it was described that the cell surface receptors CD6 and CD163 of T cells and macrophages, respectively, can recognize Grampositive and Gram-negative bacteria [7, 8]. CD5 has not been shown to bind bacteria, but its extracellular domain interacts with fungal cell wall components [9]
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