IL-33 induces IL-13-dependent cutaneous fibrosis.
IL-33 is constitutively expressed in epithelial barrier tissues, such as skin. Although increased expression of IL-33/IL-33R has been correlated with fibrotic disorders, such as scleroderma and progressive systemic sclerosis, the direct consequences of IL-33 release in skin has not been reported. To determine the effects of dysregulated IL-33 signaling in skin, we administered IL-33 s.c. and monitored its effects at the injection site. Administration of IL-33 resulted in IL-33R-dependent accumulation of eosinophils, CD3(+) lymphocytes, F4/80(+) mononuclear cells, increased expression of IL-13 mRNA, and the development of cutaneous fibrosis. Consistent with extensive cutaneous tissue remodeling, IL-33 resulted in significant modulation of a number of extracellular matrix-associated genes, including collagen VI, collagen III, and tissue inhibitor of metalloproteases-1. We establish that IL-33-induced fibrosis requires IL-13 using IL-13 knockout mice and eosinophils using Delta dblGATA mice. We show that bone marrow-derived eosinophils secrete IL-13 in response to IL-33 stimulation, suggesting that eosinophil-derived IL-13 may promote IL-33-induced cutaneous fibrosis. Collectively, our results identify IL-33 as a previously unrecognized profibrotic mediator in skin and highlight the cellular and molecular pathways by which this pathology develops.
Rankin
Andrew L
AL
Department of Immunology, Schering-Plough Biopharma, Palo Alto, CA 94304, USA.
Mumm
John B
JB
Murphy
Erin
E
Turner
Scott
S
Yu
Ni
N
McClanahan
Terrill K
TK
Bourne
Patricia A
PA
Pierce
Robert H
RH
Kastelein
Rob
R
Pflanz
Stefan
S
D000818:Animals; D002478:Cells, Cultured; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000502:physiology; D005355:Fibrosis; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000502:physiology; D007279:Injections, Subcutaneous; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000502:physiology; D018793:Interleukin-13 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D000067596:Interleukin-33; D007378:Interleukins / Q000008:administration & dosage / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D012867:Skin / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
D016326:Extracellular Matrix Proteins; C506535:Il33 protein, mouse; D018836:Inflammation Mediators; D018793:Interleukin-13; D000067596:Interleukin-33; D007378:Interleukins; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse