Radiation-induced lung injury (RILI) is the most common and major complication of chest radiotherapy, including radiation pneumonitis (RP) and radiation fibrosis (RF) (Trott et al., 2004). Acute RILI usually occurs within 3 months after chest radiotherapy. The clinical manifestations of RP are characterized by non-specific respiratory symptoms such as low-grade fever, cough and chest pain, accompanied by dyspnea in severe cases. In epidemiological studies, approximately 30 % of patients treated with chest radiotherapy exhibit RP，although, the severity of their RP occurrences varies.

The key pathogenic factor of RP is the radiation-induced generation of a diffuse, overloaded inflammatory response, and this uncontrolled inflammatory response leads to a surge in cytokine levels, and fibrosis of the lungs at a later stage (Kainthola et al., 2017, Sirav and Seyhan, 2011). At present, RP is mostly treated with glucocorticoids in clinical practice, such as prednisolone, to reduce inflammation over 4–12 weeks after exposure (Magaña and Crowell, 2003). Related studies have found that glucocorticoids alleviate the inflammatory response primarily by inhibiting the synthesis and release of inflammatory factors (Scherholz et al., 2019). However, long-term use of Glucocorticoids can lead to hyperglycemia, hypertension, coronary heart disease, and even sudden death, and in rare cases, serious side effects such as psychosis and dementia may occur (M O et al., 2016). Moreover, the immune system of cancer patients is typically already compromised by the presence of the tumor. Consequently, the administration of glucocorticoids may further impair their immune defenses, thereby elevating the risk of infections and other complications, this could potentially be one of the pivotal factors restricting its clinical application.

Alveolar macrophages (AMs) are resident macrophages in the airways and lungs, as well as the first line of defense of the respiratory tract (Ogger and Byrne, 2021). AMs are mainly classified according to their origin into tissue-resident macrophages and bone marrow-derived monocytes (Aggarwal and King, 2014). In humans, mice, and other mammals during embryonic life, AMs are derived primarily from yolk sac monocyte, and postnatal AMs develop primarily from bone marrow-derived monocytes (Evren et al., 2021a, Epelman et al., 2014). Related studies have demonstrated that inflammatory stress conditions such as infection recruit circulating monocytes into lung tissue to complement the maintenance of local immune responses (Lazarov et al., 2023, Misharin et al., 2017). However, the mechanism of monocyte-to-macrophage differentiation remains unclear. In a classic study on COVID-19, Schu et al. found by single-cell sequencing that inflammatory factors such as IL-1β, TNF-α, and IL-6 in lung tissues of patients were predominantly derived from AMs (C S et al., 2022), it is also the main cause of COVID-19. Whether the secretion of inflammatory factors in RP is dominated by AMs remains unclear. Existing studies have observed AMs phenotypic changes in RILI, such as M1 and M2, however, the molecular mechanisms underlying the changes in their cellular phenotypes still need to be further confirmed.

The NLRP3 inflammasome is a key component of the innate immune system and includes sensor protein NLRP3, adapter protein ASC, and effector protein caspase-1 (Franchi et al., 2012, Yang et al., 2019). NLRP3 activates caspase-1 and initiates the processing and release of the pro-inflammatory cytokines IL-1β and IL-18. Many studies have shown that activation of NLRP3 inflammasome in lung epithelial cells and macrophages triggers RILI and increases secretion of inflammatory factors such as IL-1β、IL-18 (Rao et al., 2023, Zhang et al., 2023). The molecular mechanisms of NLRP3 activation and action in RILI have not been elucidated, although the role of NLRP3 on macrophage polarization is now well established (Demirel et al., 2016, Grailer et al., 2014). In this research, we investigated the effect of NLRP3 on the AMs differentiation and monocyte chemotaxis in acute RILI.