Low-Dose Radiotherapy Attenuates Pulmonary Granulomas Involving Ataxia-Telangiectasia Mutated-Dependent Modulation of...

Pulmonary granulomas serve as a major obstacle in tuberculosis treatment. Low-dose radiotherapy (LDRT) emerged as a promising intervention for broad-spectrum inflammatory conditions after the COVID-19 pandemic. The therapeutic potential in mitigating pulmonary granuloma formation and progression was investigated by using a murine model induced by Mycobacterium tuberculosis-derived trehalose-6,6'-dimycolate. LDRT (0.5 Gy) significantly reduced fluorine-18-fluorodeoxyglucose uptake, lung index, and granuloma burden, while alleviating hypoxia and down-regulating hypoxia-inducible factor-1α and cell death markers (LC3B, p62, BNIP3, and caspase-3). This improvement correlated with reduced infiltration of leukocytes, macrophages, and monocytes. Mechanistically, LDRT suppressed interferon-β while enhancing IL-10 and transforming growth factor-β, independent of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. This response was mediated by a transient DNA damage response driven by the ataxia-telangiectasia mutated (ATM) protein involving phosphatidylinositol 3-kinase and ERK activation, which suppressed the pyrimidine salvage marker Tk1. Pharmacologic inhibition of ATM or its downstream effectors abrogated the LDRT-induced cytokine modulation. Notably, ATM activation with GJ071 oxalate reproduced the anti-inflammatory profile in vitro and effectively alleviated granuloma pathology in vivo, mimicking the therapeutic efficacy of LDRT. Collectively, these findings show that LDRT mitigates granuloma pathology by modulating hypoxic and inflammatory microenvironments through ATM-dependent signaling characterized by the down-regulation of interferon-β, establishing a mechanistic rationale for targeting the ATM pathway as a novel host-directed therapeutic strategy for tuberculosis.