Kwon Seokjoo, Chung Eun Joo, Kc Santwana, White Ayla O, Chung Su I, Horton Jason A, Yun Hong Shik, Ahn Heesu, Shankavaram Uma, Chung Joon-Yong, Song Joon Seon, Citrin Deborah E
Radiation Oncology Branch, Center for Cancer Research; National Cancer Institute, National Institute of Health, Bethesda, Maryland.
Department of Orthopedic Surgery, Upstate Medical University, Syracuse, New York.
Int J Radiat Oncol Biol Phys. 2025 Apr 1;121(5):1258-1270. doi: 10.1016/j.ijrobp.2024.11.103. Epub 2024 Dec 12.
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.
Mice deficient in IL-13Rα2 (Ra2 KO) and wild-type (WT) mice 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).
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 with WT mice as measured by median survival (19 vs. 21 weeks, P < .05), histology, hydroxyproline content, transforming growth factor-β expression, and macrophage accumulation. Gene sets linked to cytokine signaling and macrophage recruitment were enriched in irradiated WT compared with 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.
IL-13Rα2 is predominantly expressed in macrophages within irradiated lung and plays a crucial role in CCL2 expression, macrophage polarization, and transforming growth factor-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.
白细胞介素-13（IL-13）是辐射诱导的肺损伤（RILI）的已知介质。IL-13Rα2作为诱饵受体在拮抗IL-13信号传导中发挥公认作用。我们试图了解IL-13Rα2在RILI进展中的作用。
将缺乏IL-13Rα2的小鼠（Ra2基因敲除小鼠）和野生型（WT）小鼠每天分5次给予6 Gy胸部照射，然后观察生存情况（每组n>15）并收集组织（每组n>5）。用Masson三色染色法和羟脯氨酸含量评估肺中胶原蛋白的积累。通过RNA测序评估基因表达。用免疫组织化学法评估IL-13Rα2和巨噬细胞标志物在小鼠肺和人肺组织（n = 63）中的表达。在来自Ra2基因敲除小鼠的原代巨噬细胞培养物中以及在人单核细胞系（THP-1）的RNA沉默后，确定IL-13Rα2在IL-13介导的巨噬细胞极化中的作用。
照射后小鼠肺中膜结合的IL-13Rα2表达增加，并定位于巨噬细胞。与WT小鼠相比，照射后的Ra2基因敲除小鼠对胸部照射的敏感性降低，通过中位生存期（19对21周，P<.05）、组织学、羟脯氨酸含量、转化生长因子-β表达和巨噬细胞积聚来衡量。与Ra2基因敲除肺组织相比，与细胞因子信号传导和巨噬细胞募集相关的基因集在照射后的WT肺组织中富集。在缺乏IL-13Rα2的小鼠和人巨噬细胞中，IL-13介导的CCL2和M2标志物的表达降低。在照射后的纤维化人肺中证实了IL-13Rα2的表达增加以及与CD163的共定位。
IL-13Rα2主要在照射后肺内的巨噬细胞中表达，并且在响应IL-13时在CCL2表达、巨噬细胞极化和转化生长因子-β表达中起关键作用。这些研究证明了IL-13Rα2在RILI中意想不到的促纤维化作用，并表明靶向IL-13Rα2的策略可能改善慢性炎症和纤维化。
