Abstract
BackgroundPolymorphonuclear neutrophils (PMNs) play an important role in sepsis-related acute lung injury (ALI). Accumulating evidence suggests PMN-derived exosomes as a new subcellular entity acting as a fundamental link between PMN-driven inflammation and tissue damage. However, the role of PMN-derived exosomes in sepsis-related ALI and the underlying mechanisms remains unclear.MethodsTumor necrosis factor-α (TNF-α), a key regulator of innate immunity in sepsis-related ALI, was used to stimulate PMNs from healthy C57BL/6J mice in vitro. Exosomes isolated from the supernatant were injected to C57BL/6J wild-type mice intraperitoneally (i.p.) and then examined for lung inflammation, macrophage (Mϕ) polarization and pyroptosis. In vitro co-culture system was applied where the mouse Raw264.7 macrophages or bone marrow-derived macrophages (BMDMs) were co-cultured with PMN-derived exosomes to further confirm the results of in vivo animal study and explore the potential mechanisms involved.ResultsExosomes released by TNF-α-stimulated PMNs (TNF-Exo) promoted M1 macrophage activation after in vivo i.p. injection or in vitro co-culture. In addition, TNF-Exo primed macrophage for pyroptosis by upregulating NOD-like receptor 3 (NLRP3) inflammasome expression through nuclear factor κB (NF-κB) signaling pathway. Mechanistic studies demonstrated that miR-30d-5p mediated the function of TNF-Exo by targeting suppressor of cytokine signaling (SOCS-1) and sirtuin 1 (SIRT1) in macrophages. Furthermore, intravenous administration of miR-30d-5p inhibitors significantly decreased TNF-Exo or cecal ligation and puncture (CLP)-induced M1 macrophage activation and macrophage death in the lung, as well as the histological lesions.ConclusionsThe present study demonstrated that exosomal miR-30d-5p from PMNs contributed to sepsis-related ALI by inducing M1 macrophage polarization and priming macrophage pyroptosis through activating NF-κB signaling. These findings suggest a novel mechanism of PMN-Mϕ interaction in sepsis-related ALI, which may provide new therapeutic strategies in sepsis patients.
Highlights
Sepsis is defined as a global health priority by the World Health Organization (WHO) and characterized by excessive inflammation in response to infection, with a reported death rate of 30–45% in hospitalized patients [1, 2]
Jiao et al Crit Care (2021) 25:356 signaling. These findings suggest a novel mechanism of Polymorphonuclear neutrophils (PMNs)-Mφ interaction in sepsis-related acute lung injury (ALI), which may provide new therapeutic strategies in sepsis patients
TNF‐Exo induces lung injury by affecting M1 macrophage activation and pyroptosis in vivo Tumor necrosis factor-α (TNF-α) is a potent inducer of inflammatory response and a key regulator of innate immunity in sepsis-related ALI, which is often used to activate neutrophils [24,25,26]
Summary
Sepsis is defined as a global health priority by the World Health Organization (WHO) and characterized by excessive inflammation in response to infection, with a reported death rate of 30–45% in hospitalized patients [1, 2]. Polymorphonuclear neutrophils (PMNs) are the most abundant leukocytes in mammals, which play a crucial role in the pathogenesis of sepsis-related acute lung injury (ALI) or ARDS [4]. Exosomes are small extracellular vesicles secreted by various cell types, with size ranging from 30 to 150 nm [5] They can transfer a multitude of proteins and genetic material (including DNA, mRNA and microRNA [miRNA]) to target cells, playing a key role in cell-to-cell communications [6]. Animal studies have implicated the roles of PMN-derived exosomes in many chronic lung injuries, including chronic obstructive pulmonary disease (COPD), bronchopulmonary dysplasia and asthma [7, 8], but their role in sepsis-related ALI remains unclear. Polymorphonuclear neutrophils (PMNs) play an important role in sepsis-related acute lung injury (ALI). The role of PMN-derived exosomes in sepsis-related ALI and the underlying mechanisms remains unclear
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