Department of Immunology, Schering-Plough Biopharma, Palo Alto, CA 94304, USA.
J Immunol. 2010 Feb 1;184(3):1526-35. doi: 10.4049/jimmunol.0903306. Epub 2009 Dec 30.
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.
IL-33 在皮肤等上皮屏障组织中组成性表达。虽然 IL-33/IL-33R 的表达增加与纤维化疾病有关,如硬皮病和进行性系统性硬化症,但尚未报道 IL-33 在皮肤中的释放的直接后果。为了确定 IL-33 信号失调在皮肤中的影响,我们通过皮下给药 IL-33 并监测其在注射部位的作用。IL-33 的给药导致 IL-33R 依赖性嗜酸性粒细胞、CD3(+)淋巴细胞、F4/80(+)单核细胞的积累、IL-13 mRNA 的表达增加以及皮肤纤维化的发展。与广泛的皮肤组织重塑一致,IL-33 导致许多细胞外基质相关基因的显著调节,包括胶原 VI、胶原 III 和金属蛋白酶组织抑制剂 1。我们通过使用 IL-13 基因敲除小鼠和 Delta dblGATA 小鼠证明 IL-33 诱导的纤维化需要 IL-13 和嗜酸性粒细胞。我们表明,骨髓来源的嗜酸性粒细胞在受到 IL-33 刺激时会分泌 IL-13,这表明嗜酸性粒细胞衍生的 IL-13 可能促进 IL-33 诱导的皮肤纤维化。总的来说,我们的结果表明 IL-33 是皮肤中一种以前未被识别的促纤维化介质,并强调了这种病理发生的细胞和分子途径。