IL-31-IL-31R interactions limit the magnitude of Th2 cytokine-dependent immunity and inflammation following intestinal helminth infection.
IL-31 is a recently identified cytokine made predominantly by CD4(+) Th2 cells and its receptor, IL-31R, is expressed by a number of cell types including monocytes, epithelial cells, and T cells. Originally identified as a potential mediator of inflammation in the skin, we recently reported a novel function for endogenous IL-31R interactions in limiting type 2 inflammation in the lung. However, whether IL-31-IL-31R interactions regulate immunity or inflammation at other mucosal sites, such as the gut, is unknown. In this study, we report a regulatory role for IL-31-IL-31R interactions in the intestine following infection with the gastrointestinal helminth Trichuris muris, immunity to which is critically dependent on CD4(+) Th2 cells that produce IL-4 and IL-13. IL-31Ralpha was constitutively expressed in the colon and exposure to Trichuris induced the expression of IL-31 in CD4(+) T cells. In response to Trichuris infection, IL-31Ralpha(-/-) mice exhibited increased Th2 cytokine responses in the mesenteric lymph nodes and elevated serum IgE and IgG1 levels compared with wild type mice. IL-31Ralpha(-/-) mice also displayed enhanced goblet cell hyperplasia and a marked increase in secretion of goblet cell-derived resistin-like molecule beta into the intestinal lumen. Consistent with their exacerbated type 2 inflammatory responses, IL-31Ralpha(-/-) mice exhibited accelerated expulsion of Trichuris with significantly decreased worm burdens compared with their wild type counterparts early following infection. Collectively, these data provide the first evidence of a function for IL-31-IL-31R interactions in limiting the magnitude of type 2 inflammatory responses within the intestine.
Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Jacqueline G
JG
Perrigoue
Colby
C
Zaph
Katherine
K
Guild
Yurong
Y
Du
David
D
Artis
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020397:Goblet Cells / Q000276:immunology / Q000378:metabolism; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D007411:Intestinal Diseases, Parasitic / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D014257:Trichuriasis / Q000276:immunology* / Q000378:metabolism
D016207:Cytokines; C488159:Il31ra protein, mouse; D007074:Immunoglobulin G; D007378:Interleukins; D018123:Receptors, Interleukin; C502588:interleukin-31, mouse; D007073:Immunoglobulin E