Protective immunity to systemic infection with attenuated Salmonella enterica serovar enteritidis in the absence of IL-12 is associated with IL-23-dependent IL-22, but not IL-17.
IL-12 is essential for protective T cell-mediated immunity against Salmonella infection. To characterize the role of the related cytokine IL-23, wild-type (WT) C57BL/6 and p19(-/-) mice were infected systemically with an attenuated strain of Salmonella enterica serovar Enteritidis (S. Enteritidis). IL-23-deficient mice controlled infection with S. Enteritidis similarly as WT mice. Similar IFN-gamma production as compared with WT mice, but defective IL-17A and IL-22 production was found in the absence of IL-23. Nevertheless, although IL-23 is required for T cell-dependent cytokine responses, IL-23 is dispensable for protection against S. Enteritidis when IL-12 is present. To analyze the role of IL-23 in the absence of IL-12, low doses of S. Enteritidis were administered to p35(-/-) mice (lacking IL-12), p35/19(-/-) mice (lacking IL-12 and IL-23), p35/40(-/-) mice (lacking IL-12, IL-23, and homodimeric IL-12p40), or p35/IL-17A(-/-) mice (lacking IL-12 and IL-17A). We found survival of p35(-/-) and p35/IL-17A(-/-) mice, whereas p35/19(-/-) and p35/40(-/-) mice died within 3-6 wk and developed liver necrosis. This indicates that IL-23, but not homodimeric IL-12p40, is required for protection, which, surprisingly, is independent of IL-17A. Moreover, protection was associated with IL-22, but not IL-17F or IL-21 expression or with neutrophil recruitment. Finally, anti-IL-22 treatment of S. Enteritidis-infected p35(-/-) mice resulted in liver necrosis, indicating a central role of IL-22 in hepatocyte protection during salmonellosis. In conclusion, IL-23-dependent IL-22, but not IL-17 production is associated with protection against systemic infection with S. Enteritidis in the absence of IL-12.
Schulz
Silke M
SM
Institute of Immunology, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
Köhler
Gabriele
G
Schütze
Nicole
N
Knauer
Jens
J
Straubinger
Reinhard K
RK
Chackerian
Alissa A
AA
Witte
Ellen
E
Wolk
Kerstin
K
Sabat
Robert
R
Iwakura
Yoichiro
Y
Holscher
Christoph
C
Müller
Uwe
U
Kastelein
Robert A
RA
Alber
Gottfried
G
D000818:Animals; D005260:Female; D022781:Hepatocytes / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology*; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D008099:Liver / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D012480:Salmonella Infections / Q000235:genetics / Q000276:immunology*; D012477:Salmonella enteritidis / Q000276:immunology*; D000097043:Interleukin-22
D007371:Interferon-gamma; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D000097043:Interleukin-22