Interleukin-13 receptor subunit alpha 2 (IL-13Rα2) induces chemokine expression and macrophage polarization to promote inflammation and fibrosis

Seokjoo Kwon; Eun Joo Chung; Santwana Kc; Ayla O White; Su I Chung; Jason A Horton; Hong Shik Yun; Heesu Ahn; Uma Shankavaram; Joon-Yong Chung; Joon Seon Song; Deborah E Citrin

doi:10.1016/j.ijrobp.2024.11.103

Interleukin-13 receptor subunit alpha 2 (IL-13Rα2) induces chemokine expression and macrophage polarization to promote inflammation and fibrosis

Int J Radiat Oncol Biol Phys. 2024 Dec 11:S0360-3016(24)03710-6. doi: 10.1016/j.ijrobp.2024.11.103. Online ahead of print.

Authors

Affiliations

¹ Radiation Oncology Branch, Center for Cancer Research; National Cancer Institute, National Institute of Health, Bethesda, MD, USA.
² Department of Orthopedic Surgery, Upstate Medical University, Syracuse, NY, USA.
³ Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁴ Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
⁵ Radiation Oncology Branch, Center for Cancer Research; National Cancer Institute, National Institute of Health, Bethesda, MD, USA. Electronic address: citrind@mail.nih.gov.

PMID: 39672516
DOI: 10.1016/j.ijrobp.2024.11.103

Abstract

Purpose: Interleukin-13 (IL-13) is a known mediator of radiation induced lung injury (RILI). IL-13Rα2 has an accepted role in antagonizing IL-13 signaling by acting as a decoy receptor. We sought to understand the role of IL-13Rα2 in the progression of RILI.

Methods and materials: Mice deficient in IL-13Rα2 (Ra2 KO) and wild type mice (WT) were exposed to thoracic irradiation (IR) in 5 daily fractions of 6 Gy and followed for survival (n>15 per group) and tissue collection (n>5 per group). Collagen accumulation in the lung was evaluated with Masson's trichrome staining and hydroxyproline content. Gene expression was evaluated by RNA Sequencing. Expression of IL-13Rα2 and macrophage markers in murine lung and human lung tissue (n=63) was assessed with immunohistochemistry. The role of IL-13Rα2 in IL-13 mediated macrophage polarization was determined in primary macrophage cultures from Ra2 KO mice and after RNA silencing of a human monocyte cell line (THP-1).

Results: Membrane-bound IL-13Rα2 expression in murine lung was increased after IR and localized to macrophages. Irradiated Ra2 KO mice exhibited reduced sensitivity to thoracic IR compared to WT mice as measured by median survival (19 vs 21 weeks, p<0.05), histology, hydroxyproline content, TGF-β expression and macrophage accumulation. Gene sets linked to cytokine signaling and macrophage recruitment were enriched in irradiated WT compared to Ra2 KO lung tissue. IL-13 mediated expression of CCL2 and M2 markers was reduced in murine and human macrophages deficient in IL-13Rα2. Increased expression of in IL-13Rα2 and co-localization with CD163 was confirmed in irradiated fibrotic human lung.

Conclusions: IL-13Rα2 is predominantly expressed in macrophages within irradiated lung and plays a crucial role in CCL2 expression,macrophage polarization, and TGF-β expression in response to IL-13. These studies demonstrate an unexpected profibrotic role of IL-13Rα2 in RILI and suggest that strategies targeting IL-13Rα2 may ameliorate chronic inflammation and fibrosis.

Keywords: CCL2; IL-13Rα2; fibrosis; macrophages; radiation therapy.