CD6 binds to pathogen-associated molecular patterns and protects from LPS-induced septic shock.
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 Kd of the LPS-rsCD6 interaction was 2.69 +/- 0.32 x 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-alpha, IL6, and IL-1beta. 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.
Sarrias
Maria-Rosa
MR
Servei d'Immunologia, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain.
Farnós
Montserrat
M
Mota
Rubén
R
Sánchez-Barbero
Fernando
F
Ibáñez
Anna
A
Gimferrer
Idoia
I
Vera
Jorge
J
Fenutría
Rafael
R
Casals
Cristina
C
Yélamos
José
J
Lozano
Francisco
F
D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism* / Q000633:toxicity; D015703:Antigens, CD / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D006801:Humans; D020014:K562 Cells; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000633:toxicity; D051379:Mice; D011485:Protein Binding; D051192:Receptors, Pattern Recognition / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D012772:Shock, Septic / Q000276:immunology* / Q000517:prevention & control*; D012995:Solubility
D000942:Antigens, Bacterial; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; C062279:CD6 antigen; D008070:Lipopolysaccharides; D051192:Receptors, Pattern Recognition; D011994:Recombinant Proteins