The Th1/Th17 balance dictates the fibrosis response in murine radiation-induced lung disease

Abstract

Radiotherapy can result in lung diseases pneumonitis or fibrosis dependent on patient susceptibility. Herein we used inbred and genetically altered mice to investigate whether the tissue adaptive immune response to radiation injury influences the development of radiation-induced lung disease. Six inbred mouse strains were exposed to 18 Gy whole thorax irradiation and upon respiratory distress strains prone to pneumonitis with fibrosis presented an increased pulmonary frequency of Thelper (Th)17 cells which was not evident in strains prone solely to pneumonitis. The contribution of Th17 cells to fibrosis development was supported as the known enhanced fibrosis of toll-like receptor 2&4 deficient mice, compared to C57BL/6J mice, occurred with earlier onset neutrophilia, and with increased levels of pulmonary Th17, but not Th1, cells following irradiation. Irradiated Il17−/− mice lacked Th17 cells, and were spared both fibrosis and pneumonitis, as they survived to the end of the experiment with a significantly increased pulmonary Th1 cell frequency, only. Interferon-γ−/− mice, deficient in Th1 cells, developed a significantly enhanced fibrosis response compared to that of C57BL/6J mice. The tissue adaptive immune response influences the pulmonary disease response to radiotherapy, as an increased Th17 cell frequency enhanced and a Th1 response spared, fibrosis in mice.

Modeling and multiscale characterization of the quantitative imaging based fibrosis index reveals pathophysiological, transcriptome and proteomic correlates of lung fibrosis induced by fractionated irradiation

“…Most recently it was shown that depletion of interstitial macrophages (IMs) by a neutralizing antibody abrogating the CSF-CSF1R signaling inhibits RILF, whereas depletion of alveolar macrophages (AMs) by Clodrosome was not effective further underscoring the relevance of leukocyte subtypes in RILF development. 26 A brief collection of recent studies investigating potential impact of different leukocyte subsets in RILF [27][28][29][30][31][32][33][34][35][36] is provided in supplemental Table S1, Supporting Information. Segregated-nucleuscontaining atypical monocytes (SatM) with granulocyte characteristics regulated by CCAAT/enhancer binding protein β (C/EBPβ) as well as release of neutrophil extracellular traps (NETosis) consisting of extracellular chromatin orchestrated by peptidylarginine deiminase 4 (PAD4) in age related organ fibrosis.…”

Radiation induces changes in toll-like receptors of the uterine cervix of the rat

“…A number of studies have shown that Th17 cells and IL-17 play important roles in the development of radiation-induced functional disorders and fibrosis, e . g ., radiation-induced proctitis [4], liver fibrosis [33, 34] and radiation-induced pulmonary fibrosis [35, 36]. Interestingly, IL-10 and IL-17 levels in bronchoalveolar lavage after pulmonary irradiation were shown to be inversely correlated to the severity of pulmonary fibrosis [35].…”

Regulatory T Cells: An Emerging Player in Radiation-Induced Lung Injury

“…According to a preclinical study by Xiong et al Treg depletion attenuated lung fibrosis, which was accompanied by a significant increase in the number of Th17 cells from month 3 to 6 after irradiation (21), suggesting that Tregs may accelerate RPF through suppression of Th17 responses and that Th17 cells may exert an anti-fibrotic function in RPF. By contrast, Paun et al demonstrated that the IL-17A-deficient mice were protected from RPF, indicating a pathogenic role of Th17 cells in RPF (86).…”