Acute respiratory distress syndrome (ARDS) is defined as an acute progressive respiratory failure caused by a variety of factors [1]. It is accompanied by pulmonary tissue edema and an inflammatory response [2], with a high mortality rate of 30–50 % globally [[3], [4], [5]]. However, achieving the desired efficacy of supportive therapy is difficult because of a lack of specific and effective drugs [5]. Sepsis usually triggers ARDS [6,7], which is closely associated with an excessive inflammatory response caused by the infiltration of immune cells during early sepsis [8,9].

Macrophages are critical for regulating inflammation, injury, and repair at all pathological stages of ARDS [10,11]. Macrophages are typically polarized to a pro-inflammatory phenotype (M1) rather than an anti-inflammatory/repair (M2) phenotype, leading to the exacerbation of lung inflammation during acute lung injury (ALI) [11]. M1 macrophages promote host defense and eliminate pathogens [[12], [13], [14]]. Activated M2 macrophages, which secrete anti-inflammatory cytokines [15], are essential for immune tolerance and prevent damage to the host [16,17]. Ferroptosis is a recently discovered type of programmed cell death caused by lipid peroxidation [[18], [19], [20]]. Nuclear factor erythroid-derived 2-like 2 (Nfe2l2, also known as NRF2) is a major antioxidant transcription factor responsible for regulating intracellular redox imbalance by controlling the expression of its target genes [21]. Ferroptosis is closely associated with the inflammatory response of alveolar macrophages [22]. Ferroptosis tumor cells can affect macrophage polarization to enable immune reprogramming [22]. Therefore, the inhibition of ferroptosis and acceleration of M1/M2 macrophage transformation are potential targets for attenuating lung inflammatory injury in ALI.

Interleukin 35 (IL-35) is a newly discovered cytokine of the IL-12 heterodimeric cytokine family, which is composed of the Epstein-Barr virus-induced gene 3 (EBi3) and IL-12 p35 subunit (IL-12 a) [23,24]. IL-35 is mainly derived from lymphocytes and regulates inflammation and immune responses [23,25]. Recently, compelling research has revealed the effects of IL-35 in pulmonary inflammatory diseases, including asthma and respiratory tract infections [26,27]. However, the role and mechanism of IL-35 in regulating macrophage ferroptosis in ARDS remain unknown.

We found that rIL-35 ameliorates sepsis-induced lung injury. Mechanistically, IL-35 blocks macrophage ferroptosis through the NRF2/GPX4 signaling pathway promotes M2-type polarization while inhibiting M1-type, and enhances their phagocytosis.