CD14 mediates the innate immune responses to arthritopathogenic peptidoglycan-polysaccharide complexes of Gram-positive bacterial cell walls.
Bacterial infections play an important role in the multifactorial etiology of rheumatoid arthritis. The arthropathic properties of Gram-positive bacteria have been associated with peptidoglycan-polysaccharide complexes (PG-PS), which are major structural components of bacterial cell walls. There is little agreement as to the identity of cellular receptors that mediate innate immune responses to PG-PS. A glycosylphosphatidylinositol-linked cell surface protein, CD14, the lipopolysaccharide receptor, has been proposed as a PG-PS receptor, but contradictory data have been reported. Here, we examined the inflammatory and pathogenic responses to PG-PS in CD14 knockout mice in order to examine the role for CD14 in PG-PS-induced signaling. We found that PG-PS-induced responses in vitro, including transient increase in intracellular calcium, activation of nuclear factor-kappaB, and secretion of the cytokines tumor necrosis factor-alpha and interleukin-6, were all strongly inhibited in CD14 knockout macrophages. In vivo, the incidence and severity of PG-PS induced acute polyarthritis were significantly reduced in CD14 knockout mice as compared with their wild-type counterparts. Consistent with these findings, CD14 knockout mice had significantly inhibited inflammatory cell infiltration and synovial hyperplasia, and reduced expression of inflammatory cytokines in PG-PS arthritic joints. These results support an essential role for CD14 in the innate immune responses to PG-PS and indicate an important role for CD14 in PG-PS induced arthropathy.
Li
Xiangli
X
Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. xiangli_li@med.unc.edu <xiangli_li@med.unc.edu>
Bradford
Blair U
BU
Dalldorf
Frederick
F
Goyert
Sanna M
SM
Stimpson
Stephen A
SA
Thurman
Ronald G
RG
Makarov
Sergei S
SS
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003433:Crosses, Genetic; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology*; D018928:Immunity, Mucosal / Q000235:genetics / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010457:Peptidoglycan / Q000276:immunology*; D013154:Spleen / Q000737:chemistry / Q000166:cytology; D013297:Streptococcus pyogenes / Q000737:chemistry
D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D016328:NF-kappa B; D010457:Peptidoglycan; D002118:Calcium