Sepsis is a fatal infection mainly attributed to bacterial infections and causes substantial morbidity and mortality worldwide [1,2]. It is characterized by the uncontrollable release of pro-inflammatory cytokines, resulting in multi-organ injury, including lung tissues [3,4]. Lipopolysaccharide (LPS), a gram-negative bacterial endotoxin, is responsible for the initiation of the inflammatory response and associated sepsis via binding with its receptor toll-like receptor-4 (TLR4) [5]. Macrophages are innate immune cells that play important roles in modulating various physiological and pathological processes [6]. In response to LPS and interferon-γ (IFN-γ), macrophages undergo pro-inflammatory differentiation (M1 phenotype), which is characterized by releasing of various cytokines, including tumor necrosis factor α (TNF-α), interleukin (IL)-6, and IL-1β [7]. These M1 polarized macrophages and their derived cytokines drive adaptive immune responses and pathological damage. While IL-4- and IL-13-induced M2 macrophages produce many anti-inflammatory cytokines, such as arginase 1 (Arg-1) and IL-10, which is responsible for wound healing and inflammation resolution [6,8,9]. Many studies have emphasized the critical role of M2 macrophages in improving infectious and non-infectious conditions [10]. Hence, development of drugs that induce M2 macrophages may provide new strategy for cure of inflammatory diseases such as sepsis [11].

Previous studies have demonstrated that cellular homeostasis and several signaling pathways together drive the differentiation of macrophages toward the M1 or M2 phenotypes [12]. Moreover, the redox balance has been implicated in shaping the role of macrophages during the onset, progression, and resolution of the inflammatory response [13]. Briefly, pro-oxidants or increased reactive oxygen species (ROS) levels boost macrophage pro-inflammatory differentiation, while antioxidants or reduced ROS levels facilitate macrophage anti-inflammatory differentiation [[14], [15], [16]]. Moreover, several transcription regulators are involved in regulating the expression of pro-inflammatory cytokines, such as cyclooxygenase 2 (COX2), nuclear factor-κB (NF-κB) in macrophages [17]. Peroxisome proliferator-activated receptor-γ (PPAR-γ) drive macrophages toward the M2 phenotype by modulating the expression of anti-inflammatory genes, including Arg1 and Il10. Moreover, signal transducer and activator of transcription 6 (STAT6) also plays crucial role in modulating IL-4-induced macrophage anti-inflammatory differentiation [18,19]. Therefore, we speculated that targeting STAT6 and PPAR-γ may alleviate inflammatory responses in vivo and in vitro.

Recent studies have suggested that physical exercise inhibits oxidative damage and inflammation response in various pathological conditions, including sepsis, diabetes, obesity, cardiovascular, and Alzheimer's disease [20,21]. However, the mechanism underlying exercise-mediated anti-inflammatory effects remains unclear. In response to acute strenuous exercise, skeletal muscles and cardiomyocytes robustly produce large amounts of irisin, which is cleaved from fibronectin type III domain-containing protein 5 (FNDC5) [22]. Irisin administration alters mitochondrial homeostasis, fatty acid oxidation, glucose metabolism, and fat browning after binding to its receptor integrin αVβ5. In a population comprising patients with obesity and sepsis, serum irisin levels are remarkably lower than those in a healthy population [23]. Moreover, increased irisin levels improve several metabolic and non-metabolic diseases [24]. Whereas, the potential character and mechanism of irisin in regulating macrophage anti-inflammatory differentiation remains unclear.

In the current study, we aimed to investigate whether exogenous irisin administration can promote M2 macrophage polarization and alleviate lung damage in LPS-induced septic mice. Moreover, the underlying molecular mechanisms involved in the irisin-mediated anti-inflammatory responses were explored in depth. Our study may provide novel insights into irisin-mediated anti-inflammatory response, which may be a promising therapeutic strategy against inflammatory diseases.