Early activation of the interleukin-23-17 axis in a murine model of oropharyngeal candidiasis.
Candida albicans is an oral commensal yeast that causes oropharyngeal candidiasis (OPC) in immunocompromised individuals. The immunological pathways involved in OPC have been revisited after the interleukin-17 (IL-17) pathway was implicated in fungal immunity. We studied immediate (<24 h) and adaptive (3-6 day) IL-12 and IL-23-17 pathway activation in naive p40(-/-) mice, which lack IL-12 and IL-23 and develop severe, chronic OPC upon oral inoculation with C. albicans. Macrophages from p40(-/-) mice were less efficient than C57BL/6J controls at killing C. albicans in vitro but very low numbers in the oral mucosae of infected C57BL/6J mice suggest that they are not critical in vivo, at least in this strain. Migration of macrophages to regional lymph nodes of infected p40(-/-) mice was impaired; however, dendritic cell migration was not affected. Recombinant IL-12 therapy provided only temporary relief from OPC, suggesting that IL-23 is required for full protection. In C57BL/6J mice, but not p40(-/-) mice, messenger RNAs encoding IL-23p19 and IL-17 were induced in the oral mucosa within 24 h of infection (6 ± 0.6 and 12 ± 2.7-fold). By day 6 of infection in C57BL/6J mice, IL-17A messenger RNA level had increased 5.1 ± 1.8 and 83 ± 21-fold in regional lymph nodes and oral tissues respectively. Ablation of p40 was associated with delayed or abrogated induction of IL-17A pathway targets (monocyte chemoattractant protein-1, IL-6 and macrophage inflammatory protein-2), and a lack of organized recruitment of neutrophils to the infected oral mucosa. Overall our data show that the IL-23-17A axis is activated early in the oral mucosae of immunologically naive mice with OPC.
Saunus
J M
JM
School of Dentistry, the University of Queensland, Brisbane, Australia.
Wagner
S A
SA
Matias
M A
MA
Hu
Y
Y
Zaini
Z M
ZM
Farah
C S
CS
D000818:Animals; D002180:Candidiasis, Oral / Q000235:genetics / Q000276:immunology*; D018932:Chemokine CCL2 / Q000276:immunology; D054426:Chemokine CXCL2 / Q000276:immunology; D002908:Chronic Disease; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007113:Immunity, Innate; D018664:Interleukin-12 / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000172:deficiency; D020381:Interleukin-17 / Q000276:immunology*; D053759:Interleukin-23 / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009061:Mouth Mucosa / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D010587:Phagocytosis; D011994:Recombinant Proteins; D013047:Specific Pathogen-Free Organisms; D057705:Transendothelial and Transepithelial Migration
D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D053759:Interleukin-23; D011994:Recombinant Proteins; D018664:Interleukin-12