The role of toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis.
Toll-like receptors (TLRs) represent the main class of pattern-recognition receptors involved in sensing pathogenic microorganisms. The aim of the present study was to assess the role of TLR4 in the defense against Candida albicans infection. The outgrowth of C. albicans was 10-fold higher in TLR4-defective C3H/HeJ mice, compared with that in control C3H/HeN mice (P<.05). Production of tumor necrosis factor (TNF) and interleukin (IL)-1alpha and IL-1beta by mouse macrophages in response to C. albicans stimulation was not affected by TLR4, and the candidacidal capacities of the neutrophils and macrophages of C3H/HeJ mice were normal. In contrast, production of the CXC chemokines KC and macrophage inhibitory protein-2 was 40%-60% lower by the macrophages of C3H/HeJ mice (P<.05), which resulted in a 40% decrease in neutrophil recruitment to the site of infection. Candida-induced TNF and IL-1beta production by human peripheral blood mononuclear cells was significantly inhibited by blocking anti-TLR2 antibodies in vitro. In conclusion, TLR4-defective C3H/HeJ mice are more susceptible to C. albicans infection, and this is associated with impaired chemokine expression and neutrophil recruitment.
Netea
Mihai G
MG
Department of Medicine, Division of General Internal Medicine, University Medical Center St. Radboud, Nijmegen, The Netherlands.
Van Der Graaf
Chantal A A
CA
Vonk
Alieke G
AG
Verschueren
Ineke
I
Van Der Meer
Jos W M
JW
Kullberg
Bart Jan
BJ
D000818:Animals; D002176:Candida albicans / Q000302:isolation & purification; D002177:Candidiasis / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D002452:Cell Count; D018925:Chemokines / Q000096:biosynthesis; D019743:Chemokines, CXC / Q000096:biosynthesis; D029721:Drosophila Proteins; D007375:Interleukin-1 / Q000032:analysis; D007668:Kidney / Q000382:microbiology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000502:physiology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D010587:Phagocytosis; D017354:Point Mutation; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D018925:Chemokines; D019743:Chemokines, CXC; D029721:Drosophila Proteins; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha