Radiation-Induced Pulmonary Fibrosis (RIPF) Is Mediated By Interleukin 13 Receptor Subunit Alpha 2 (IL13Ra2)

Abstract

Radiation induced pulmonary fibrosis (RIPF) is a late toxicity of thoracic radiotherapy. Type 2 immune responses driven by IL-13 have recently been implicated in the pathogenesis of RIPF, in part through interaction with the heterodimeric IL-13Ra1/IL4Rα receptor complex. Although its mechanism is not clearly understood, IL-13Rα2 is a transmembrane receptor thought to function as a decoy receptor for IL-13. In this study, we sought to characterize the role of IL13Rα2. Recent evidence implicates IL-13Rα2 in signaling of chitinases produced in type 2 inflammatory responses, which play a role in RIPF initiation and progression. The 10 week old C57BL6/NcR (WT) and IL13Ra2 deficient [C57BL/6-[Ko]IL13Rα2 (IL-13Rα2-/-)] mice were exposed to 5 daily 6 Gy fractions of thoracic radiation (RT). Lung tissue was collected at 16 weeks after RT. Collagen accumulation was measured with hydroxyproline content and accumulation of total and alternatively activated (M2) macrophages was assessed with immunohistochemistry. Bone marrow derived macrophages (BMDM) from each strain were treated with IL-13. Gene expression in RNA isolated from lung tissue and BMDM was evaluated with quantitative RT-PCR and PCR array. Deficiency of IL13Rα2 significantly extended survival significantly after thoracic irradiation compared to WT mice (19 vs. 21 weeks, p=0.03 log rank). WT mice developed confluence of fibrosis, increased hydroxyproline content, and accumulation of M2 macrophages after RT. IL-13Ra2-/- mice had no observable increase in hydroxyproline content after RT and had no evidence of macrophage accumulation when compared to unirradated controls. The expression of fibrosis-associated cytokines and chemokines (Ccl2, Timp1, and IL-6) was suppressed in irradiated IL-13Ra2-/-lung compared to WT. WT macrophages isolated from whole lung expressed increased levels both soluble and membrane bound isoforms of IL13Rα2 after radiation. BMDM from IL-13Ra2-/- mice treated with IL-13 had suppressed expression of Ccl11, Timp1, and Pdgfb compared to BMDM from WT mice. Our data show that IL-13Rα2 deficiency attenuates RIPF, and that this protection is accompanied by decreased accumulation of macrophages and altered production of inflammatory cytokines and chemokines by macrophages. Whether the protective benefit of IL-13Rα2 deficiency is attributable to absent decoy-receptor function is currently being investigated.