Bronchopulmonary dysplasia (BPD) is a severe respiratory disorder that markedly impacts the survival [1] and long-term outcomes of preterm infants and is pathologically characterized by impaired alveolar development and pulmonary microvascular dysplasia [2]. The immature lung initiates an inflammatory cascade in response to multiple insults, including intrauterine and postnatal ventilator-induced injury, oxygen toxicity, and infections, all of which contribute to the pathogenesis of BPD [3]. Although the general mechanisms underlying these inflammatory responses are relatively well understood, the specific regulatory pathways involved remain incompletely defined. Consequently, understanding how inflammation is regulated in BPD remains essential. Continued research in this area may reveal additional treatment possibilities that can aid in regulating or inhibiting the disease.

Multiple cellular interactions within the pulmonary microenvironment contribute to inflammatory pathway activation in BPD [4]. Alveolar macrophages (AMs) serve an essential function in the pathophysiological development of BPD. As the predominant population of macrophages exerting biological functions in the lung, AMs are the principal effecter cells of the innate immune response [5]. AMs are key regulators of the local inflammatory microenvironment and response; upon stimulation by pathogenic factors, they release a multitude of inflammatory mediators that trigger a cascade of amplified responses, contributing to lung injury [6]. Inflammation induced by activated macrophages serves a pivotal function in the development of BPD [7]. Depending on signals from the surrounding microenvironment, macrophages may polarize into pro-inflammatory M1 types or anti-inflammatory and tissue-repairing M2 types [8]. AMs contribute to the pathogenesis of BPD, in which a shift to the M1 phenotype and a decrease in M2 polarization are strongly associated with disease progression [9]. An imbalance in the M1/M2 macrophage ratio may exacerbate inflammatory injury in the lungs [10]. Phagocytosis by AMs is crucial for the preservation of lung homeostasis, and dysfunction in their phagocytic activity may contribute to the persistence of lung inflammation [11]. However, the specific cytokines involved in regulating AMs polarization and phagocytosis in BPD remain unidentified.

Interferon Regulatory Factor 4 (IRF4), an essential component of the interferon regulatory factor (IRF) transcription factor family, serves a fundamental function in immune system processes and contributes to the developmental and functional control of diverse immune cell populations [12]. IRF4 exerts regulatory influence on immune responses by orchestrating the developmental progression and functional specialization of T cells, B cells, dendritic cells, and macrophages [13]. Through its control over immune cell differentiation and maturation, IRF4 exhibits connections to asthma progression, autoimmune disorders, and hematologic cancers [[14], [15], [16]]. Recent investigations have demonstrated the significant impact of IRF4 in regulating macrophage polarization within ischemia-reperfusion injury mice models [17,18]. Disrupted activation of the CSF-1/IRF4 signaling cascade inhibits macrophage transition from inflammatory M1 status to anti-inflammatory M2 status, leading to persistent M1-mediated inflammatory conditions [19]. Notably, enhanced IRF4 expression promotes M2 polarization and demonstrates protective capabilities against restenosis following arterial damage [20]. In contrast, suppression of IRF4 expression limits M2 polarization, which may help to attenuate the progression of emphysema [21]. Nevertheless, the specific function of IRF4 in BPD development remains partially undefined, and it remains unclear whether IRF4 influences the pathological process of BPD by modulating the polarization and phagocytic function of AMs. Consequently, the objective of this study was to investigate the role of IRF4 in the inflammatory response associated with BPD by modulating the polarization and phagocytic function of AMs, utilizing both a hyperoxia-induced mice model of BPD and a hyperoxia-exposed MH-S alveolar macrophage cell model.