IRG1/itaconate alleviates acute liver injury in septic mice by suppressing NLRP3 expression and its mediated macrophage pyroptosis via regulation of the Nrf2 pathway

Sepsis is a systemic inflammatory response triggered by infection. It can result in shock and multi-organ dysfunction in severe cases, with a mortality rate of 15–20 % [1], [2]. As the largest glandular organ in the human body, the liver has a rich blood supply and plays a crucial role in maintaining metabolic and immune homeostasis. However, it is one of the most commonly affected organs during sepsis [3]. Acute hepatic injury can occur at any stage of sepsis and is a vital indicator of the progression of multiple organ dysfunction syndrome [4]. Moreover, liver injury can impair the ability of the body to eliminate bacteria or lipopolysaccharide (LPS), which is a standalone predictor of multiple organ failure and mortality. Therefore, promptly correcting hepatic dysfunction can enhance patient prognosis [5]. Antibiotics and glucocorticoids are not administered for extended periods during the clinical management of sepsis, owing to their adverse effects and potential drug dependency [6], [7], [8]. Despite the implementation of contemporary intensive care units that have markedly enhanced the survival rates of patients with sepsis, effective prevention and intervention measures remain insufficient. Therefore, it is vital to investigate the pathogenesis of sepsis-induced acute liver injury and identify effective therapeutic targets and drugs to enhance clinical treatment.

Macrophages protect against immunomodulatory activity by reducing tissue and organ damage during sepsis [9]. They maintain normal liver function, promote the onset of liver injury, and contribute to the preservation of homeostasis during. Macrophage pyroptosis is a form of inflammatory cell death that predominantly releases inflammatory mediators to cause macrophage death, thus provoking an overwhelming inflammatory response. The P2Y14 receptor relieves rheumatoid arthritis by inhibiting macrophage pyroptosis [10], whereas the purinergic receptor P2X7 promotes the progression of abdominal aortic aneurysms by regulating macrophage pyroptosis [11]. However, whether the inhibition of macrophage pyroptosis in sepsis attenuates liver injury remains unknown. Our study identified a considerable protective effect against sepsis-induced liver injury following the reduction of macrophage pyroptosis. This indicates that macrophage pyroptosis inhibition could have potential applications in the treatment of septic liver injury. However, the precise mechanism requires further investigation.

Cellular pyroptosis is a naturally occurring immune process that leads to pro-inflammatory cell death in vertebrates. Pattern recognition receptors recognize a range of pathogen-associated molecular patterns that activate the protease activity of the caspase-1 precursor, causing it to self-cleave and produce mature caspase-1, which mediates cellular pyroptosis [12], [13]. Inflammatory vesicles are intracellular complexes comprising multiple protein types, including the NLRP3 inflammatory vesicles. The constituent proteins of NLRP3 inflammatory vesicles include the core protein NLRP3, articulin ASC, protein kinase NEK7, and effector protein caspase-1. The core protein NLRP3 contains three structural domains. The amino-terminal end contains the PYD structural domain that contains the LRR structural domain. The carboxy-terminal end contains the LRR domain, and the middle contains the NACHT domain. NEK7 mediates the NLRP3 zwitterionic response and inflammasome activation by interacting with NLRP3 [14], [15], [16]. After NLRP3 inflammasome activation, activated caspase-1 breaks down precursors of IL-1β, IL-18, and gasdermin D to produce their active components. Several stimuli, as well as metabolites such as mitochondrial reactive oxygen species (ROS) and β-hydroxybutyric acid ketone produced during low-glucose states, can activate NLRP3 inflammatory vesicles [17], [18], [19].

Itaconate is an unsaturated dicarboxylic acid obtained through the IRG1-catalyzed decarboxylation of cis-aconitic acid in the tricarboxylic acid cycle [20]. In macrophages, itaconate production is the primary metabolic reprogramming mechanism that regulates the cellular immune response as LPS increases macrophage clathrin production. Endogenous itaconate and its cell-permeable derivative, 4-octyl itaconate, react with cysteine residues in several proteins to induce substantial anti-inflammatory effects [21], [22]. Patients with sepsis frequently experience oxidative stress caused by an imbalance between ROS generation and the antioxidant defense system, leading to ROS overproduction [23], [24]. Previous studies have shown the involvement of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in the regulation of oxidative stress [25], [26]. However, the precise mechanism by which it influences septic liver injury remains unclear. Therefore, the objective of the present study was to examine the potential role of IRGI in immune modulation, specifically its impact on NLRP3 inflammatory vesicle activation and macrophage pyroptosis. This study further aimed to identify the related regulatory mechanisms.

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