CSF1R inhibition prevents radiation pulmonary fibrosis by depletion of interstitial macrophages

Abstract

Radiation-induced lung fibrosis (RIF) is a delayed side-effect of chest radiotherapy, frequently associated with macrophage infiltration.We aimed to characterise the role of pulmonary macrophages in RIF using human lung biopsies from patients receiving radiotherapy for thorax malignancies and a RIF model developed in C57BL/6 mice after 16-Gy thorax irradiation.High numbers of macrophages (both interstitial and alveolar) were detected in clinical and preclinical RIF. In the preclinical model, upregulation of T-helper (Th)2 cytokines was measured, whereas Th1 cytokines were downregulated in RIF tissue lysate. Bronchoalveolar lavage demonstrated upregulation of both types of cytokines. At steady state, tissue-infiltrating macrophages (IMs) expressed 10-fold more arginase (Arg)-1 than alveolar macrophages (AMs), and a 40-fold upregulation of Arg-1 was found in IMs isolated from RIF. IMs, but not AMs, were able to induce myofibroblast activation In addition, whereas depletion of AMs using Clodrosome didn't affect RIF score, depletion of IMs using a clinically available colony-stimulating factor receptor-1 (CSF1R) neutralising antibody was antifibrotic.These findings suggest differential contributions of alveolar interstitial macrophages in RIF, highlighting the fibrogenic role of IMs. The CSF1/CSF1R pathway was identified as a new therapeutic target to inhibit RIF.

Macrophages in radiation injury: a new therapeutic target

“…9 Accordingly, in our recent study, we showed that lung alveolar macrophages (AM) that are newly recruited to the lungs after the depletion induced by thoracic IR exposure are activated, as they present an increase in both the expression of Arg1, CD206 and Icam1. 8 This result suggests that these AMs, which have not been directly exposed to IR, are activated by the existing signals rather than directly by IR. However, several in vitro studies underscore the direct effect of IR in macrophage activation.…”

“…12 Several studies have described the secretion of inflammatory cytokines after IR in vivo . 4,8 Inflammatory cytokines produced in vivo by irradiated cells could act as bystander factors to induce the abscopal effect. Interestingly, macrophages have been proposed as an important source of bystander signals in vivo .…”

“…14 Accordingly, after IR, macrophages are recruited at the irradiated site. 4,8 The direct effect of IR on macrophages remains poorly explored. 15 Mukherji et al proposed that macrophage activation is a secondary effect of IR, which results from cellular damage signals and the clearance of radiation-induced apoptotic cells, rather than a direct effect of IR.…”

“…Upon activation, macrophages produce bystander signals 9 and play an important role in the development of radiation injury. 8 Interestingly, RT can strongly affect the activated phenotypes of macrophages and thus shape the macrophage response and role. Rubin and colleagues have shown that isolated AMs from lungs of mice that were irradiated (17.5 Gy) in vivo produce large amounts of TGFα and TGFβ, suggesting that in response to a high dose of IR, resident and recruited macrophages were stimulated to produce profibrotic growth factors that would induce the differentiation of fibroblasts into secretory myofibroblasts.…”

“…During the radiation wound repair process, recruitment of inflammatory cells occurs at the site of injury, which can contribute to late tissue damage. 6–8 Here, we discuss in more detail the immune system/macrophage responses to radiotherapy and their involvement in the development of radiation injury.…”