Resistin-like molecule α promotes pathogenic Th17 cell responses and bacterial-induced intestinal inflammation.
Resistin-like molecule (RELM)α belongs to a family of secreted mammalian proteins that have putative immunomodulatory functions. Recent studies have identified a pathogenic role for RELMα in chemically induced colitis through effects on innate cell populations. However, whether RELMα regulates intestinal adaptive immunity to enteric pathogens is unknown. In this study, we employed Citrobacter rodentium as a physiologic model of pathogenic Escherichia coli-induced diarrheal disease, colitis, and Th17 cell responses. In response to Citrobacter, RELMα expression was induced in intestinal epithelial cells, infiltrating macrophages, and eosinophils of the infected colons. Citrobacter-infected RELMα(-/-) mice exhibited reduced infection-induced intestinal inflammation, characterized by decreased leukocyte recruitment to the colons and reduced immune cell activation compared with wild-type (WT) mice. Interestingly, Citrobacter colonization and clearance were unaffected in RELMα(-/-) mice, suggesting that the immune stimulatory effects of RELMα following Citrobacter infection were pathologic rather than host-protective. Furthermore, infected RELMα(-/-) mice exhibited decreased CD4(+) T cell expression of the proinflammatory cytokine IL-17A. To directly test whether RELMα promoted Citrobacter-induced intestinal inflammation via IL-17A, infected WT and IL-17A(-/-) mice were treated with rRELMα. RELMα treatment of Citrobacter-infected WT mice exacerbated intestinal inflammation and IL-17A expression whereas IL-17A(-/-) mice were protected from RELMα-induced intestinal inflammation. Finally, infected RELMα(-/-) mice exhibited reduced levels of serum IL-23p19 compared with WT mice, and RELMα(-/-) peritoneal macrophages showed deficient IL-23p19 induction. Taken together, these data identify a proinflammatory role for RELMα in bacterial-induced colitis and suggest that the IL-23/Th17 axis is a critical mediator of RELMα-induced inflammation.
Institute of Immunology, Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Lisa C
LC
Osborne
Karen L
KL
Joyce
Theresa
T
Alenghat
Gregory F
GF
Sonnenberg
Paul R
PR
Giacomin
Yurong
Y
Du
Kirk S
KS
Bergstrom
Bruce A
BA
Vallance
Meera G
MG
Nair
D056704:Adaptive Immunity / Q000187:drug effects; D000818:Animals; D044082:Citrobacter rodentium / Q000276:immunology* / Q000472:pathogenicity; D016264:Dextran Sulfate; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D053760:Interleukin-23 Subunit p19 / Q000097:blood / Q000276:immunology; D007422:Intestines / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology
D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D011994:Recombinant Proteins; C413576:Retnla protein, mouse; D016264:Dextran Sulfate