CD6 binds to pathogen-associated molecular patterns and protects from LPS-induced septic shock

Abstract

CD6 is a lymphocyte receptor that belongs to the scavenger receptor cysteine-rich superfamily. Because some members of the scavenger receptor cysteine-rich superfamily act as pattern recognition receptors for microbial components, we studied whether CD6 shares this function. We produced a recombinant form of the ectodomain of CD6 (rsCD6), which was indistinguishable (in apparent molecular mass, antibody reactivity, and cell binding properties) from a circulating form of CD6 affinity-purified from human serum. rsCD6 bound to and aggregated several Gram-positive and -negative bacterial strains through the recognition of lipoteichoic acid and LPS, respectively. The K d of the LPS-rsCD6 interaction was 2.69 ؎ 0.32 ؋ 10 ؊8 M, which is similar to that reported for the LPS-CD14 interaction. Further experiments showed that membrane CD6 also retains the LPS-binding ability, and it results in activation of the MAPK signaling cascade. In vivo experiments demonstrated that i.p. administration of rsCD6 before lethal LPS challenge significantly improved mice survival, and this was concomitant with reduced serum levels of the proinflammatory cytokines TNF-␣, IL6, and IL-1␤. In conclusion, our results illustrate the unprecedented bacterial binding properties of rsCD6 and support its therapeutic potential for the intervention of septic shock syndrome or other inflammatory diseases of infectious origin.bacterial cell component ͉ innate immunity ͉ lymphocyte surface receptor

Structural Basis of Recognition of Pathogen-associated Molecular Patterns and Inhibition of Proinflammatory Cytokines by Camel Peptidoglycan Recognition Protein

“…These were reduced by Ͼ90% with 5 g/ml CPGRP-S. These data clearly indicate that CPGRP-S neutralizes effectively the proinflammatory effects of LPS and LTA in vitro presumably by blocking the availability of LPS and LTA to various PAMP receptors (CD14, Toll-like receptors, and CD6) expressed on T cells, which are known to recognize LPS/LTA (19,20).…”

“…They participate in the pathogenesis of sepsis (18) by producing copious amounts of TNF-␣ and IL-6 predominantly in macrophages and T cells (19,20). The levels of TNF-␣ were increased by ϳ3.5-fold ( Fig.…”

Molecular and Functional Characterization of Mouse S5D-SRCRB: A New Group B Member of the Scavenger Receptor Cysteine-Rich Superfamily

“…In some instances, the amino acid sequence motifs involved in SRCR-mediated pathogen recognition have been precisely identified (RxR, VEVLxxxxW) (15,16,20), but an exact match to these motifs is not observed among any of the SRCR domains of S5D-SRCRB. However, by no means does this exclude the SRCR domains of mouse S5D-SRCRB as being responsible for pathogen recognition, as exemplified by Spa, CD6, and CD5 (17)(18)(19). The SRCR domains are among the few protein modules from which evolution has settled a myriad of structurally related but functionally different proteins.…”

“…They do not possess enzymatic activity; however, some SRCR domains have been involved in protein-protein interactions, the best studied examples being those of CD6 with CD166/ALCAM (4) and CD163 with the haptoglobin-hemoglobin complex (14). In recent years, a number of studies also supported the recognition of PAMPs by some, but not all, group A (i.e., MARCO) (15) and B (i.e., DMBT1/SAG/gp340, Spa, CD6, CD5, and CD163) (16)(17)(18)(19)(20) SRCR-SF members. Group B is composed of about a dozen members expressed in mammals by immune cells, such as macrophages (i.e., CD163/M130, CD163L1/M160, Spa/AIM) or lymphocytes (i.e., CD5, CD6, SCART, WC1), as well as by cells of the gastrointestinal, respiratory, and genitourinary tracts (i.e., DMBT1/ SAG/gp340, S4D-SRCRB, 18-B) (5,21).…”

The Novel Lipopolysaccharide-Binding Protein CRISPLD2 Is a Critical Serum Protein to Regulate Endotoxin Function

“…Of note is CD6, belong to the scavenger receptor cysteine-rich superfamily, which is readily expressed on the surface of lymphocytes but maintains a low serum concentration (16). It exhibits significant LPS-binding affinity, and its soluble form has been shown to inhibit the induction of endotoxic shock in mice (17). Passively administered LPS-reactive Abs have also been shown to ameliorate Gramnegative sepsis (18 -20).…”