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IL-33 Induces IL-13–Dependent Cutaneous Fibrosis

Andrew L. Rankin,^* John B. Mumm, Erin Murphy, Scott Turner, Ni Yu, Terrill K. McClanahan, Patricia A. Bourne, Robert H. Pierce, Rob Kastelein,^* and Stefan Pflanz^*

^*Department of Immunology, Department of Oncology, and Department of Experimental Pathology and Pharmacology, Schering-Plough Biopharma, Palo Alto, CA 94304

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 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.

Address correspondence and reprint requests to Dr. Stefan Pflanz, Schering-Plough Biopharma, 901 California Avenue, Palo Alto, CA 94304. E-mail address: stefan.pflanz{at}spcorp.com

The online version of this article contains supplemental material.

Abbreviations used in this paper:

bmEos, bone marrow-derived eosinophils; Ct, cycle threshold; DAMP, damage-associated molecular pattern; ECM, extracellular matrix; KO, knockout; MMP, matrix metalloprotease; MSA, mouse serum albumin; Mut, mutant; TIMP, tissue inhibitor of metalloproteases; WT, wild type.

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