Sepsis is one of the leading causes of mortality worldwide, and it is the immediate cause of death for critical patients (Srzić et al., 2022). The 2020 Institute for Health Metrics and Evaluation’s Global Burden of Sepsis study estimated 48.9 million incident sepsis cases worldwide in 2017. A recent systematic review and analysis showed that the in-hospital case fatality rate for global hospital-treated sepsis reached 26.7% (Fleischmann-Struzek and Rudd, 2023). Sepsis was defined as a clinical syndrome that presented as a systemic inflammatory response syndrome (SIRS) caused by infection, it may eventually develop into a life-threatening organ dysfunction (Salomão et al., 2019). In this process, lung is the first and most vulnerable organ targeted by infection. About half of sepsis patients suffered from acute lung injury. Sepsis-induced acute lung injury (SALI) involved various factors, including inflammation, oxidative stress, and genetics (Sun et al., 2023). Macrophages in the lung played a crucial role in maintaining pulmonary immune homeostasis. During the development of inflammation, the function of macrophage changed with the alteration of their polarization phenotype, and subsequently regulated the acute lung injury (Wang et al., 2023). Therefore, targeting macrophage polarization has the potential to alleviate inflammation and promote lung repair in SALI.
Sepsis led to an imbalance in reactive oxygen species and active nitrogen levels, disrupting redox homeostasis and exacerbating oxidative stress (Joffre and Hellman, 2021). In addition, oxidative stress is also an important factor in triggering inflammation (Nagar et al., 2018). Flavoproteins is a protein family widely involved in cellular redox pathways (Jortzik et al., 2014). Therefore, we speculated that the flavoprotein family may play a potential role in the pathogenesis of sepsis. The members of flavoprotein family that may be involved in SALI were identified by analyzing the datasets GSE130936 and GSE154918 from the GEO database, along with genes associated with lung injury, macrophage polarization, and inflammation obtained from the GeneCards database. QSOX1 (quiescin Q6 sulfhydryl oxidase 1), a member of the flavoprotein family, had great potential for inhibiting macrophage polarization.
QSOX1, a sulfhydryl oxidase, knockdown promoted the expression of the macrophage marker CD68 and pro-inflammatory factors in the heart tissues induced by isoproterenol, thereby exacerbating endoplasmic reticulum stress, oxidative stress, and inflammation in the heart tissues. Studies showed that QSOX1 interacted with the epidermal growth factor receptor (EGFR) to promote EGFR ubiquitination and endosomal transport. The effects of QSOX1 led to the rapid degradation of EGFR in the cytoplasm (Sun et al., 2021). Induction of lipopolysaccharide (LPS) promoted the expression on the cell surface and phosphorylation of EGFR in bone marrow-derived macrophages (BMDM). The EGFR phosphorylation inhibitor Erlotinib antagonized this process and prevented macrophage M1 polarization. Erlotinib administration reduced markers of M1-type macrophages in the bronchoalveolar lavage fluid (BALF) of SALI mice induced by LPS and cecal puncture (CLP) in vivo (Zhang et al., 2022). Therefore, the regulatory effect of QSOX1 on EGFR may target to prevent macrophage M1 polarization in the sepsis model. Based on the GSE130936 and GSE154918 datasets, QSOX1 expression was elevated in the lung tissues of LPS-induced mice and blood samples from sepsis patients. Currently, the role of QSOX1 in SALI is rarely reported.
In this study, the SALI model in mice and inflammation model in RAW264.7 cells were constructed through LPS induction. The expression of QSOX1 in RAW264.7 cells was regulated by infection with lentivirus carrying the vector targeting QSOX1. This study aimed to elucidate the effect of QSOX1 on macrophage M1 polarization and to provide molecular targets for the prevention and treatment of SALI.