Pyroptosis is a form of cell death triggered by the innate immune system that has been implicated in the pathogenesis of sepsis and acute lung injury. At the cellular level, pyroptosis is characterized by cell swelling, membrane rupture, and release of inflammatory cytokines, such as IL-1β. However, the role of endogenous lipids in pyroptosis remains underappreciated. We discovered that 4-hydroxynonenal (HNE), a major endogenous product of lipid peroxidation, inhibited pyroptosis and inflammasome activation. HNE at physiological concentrations (3 µM) blocked nigericin and ATPinduced cell death, as well as secretion of IL-1β, by mouse primary macrophages and human peripheral blood mononuclear cells. Treatment with HNE, or an increase of endogenous HNE by inhibiting glutathione peroxidase 4, reduced inflammasome activation in mouse models of acute lung injury and sepsis. Mechanistically, HNE inhibited the NLRP3 inflammasome activation independently of Nrf2 and NF-κB signaling, and had no effect on the AIM2 inflammasome. Furthermore, HNE directly bound to NLRP3 and inhibited its interaction with NEK7. Our findings identify HNE as a novel, endogenous inhibitor of the NLRP3 inflammasome. and the final effector downstream of caspase-1 activation. Active caspases cleave GSDMD to generate an N-terminal cleavage product (GSDMD-NT) that forms transmembrane pores to enable IL-1β release and to drive pyroptosis (10-12). The importance of IL-1β as a disease mediator was confirmed by the CANTOS trial in which an IL-1β neutralizing antibody led to a lower rate of recurrent cardiovascular events in patients with previous myocardial infarction (13).Recent data suggest that endogenous lipids or their oxidation products can activate or inhibit the assembly of inflammasomes (5, 14). Among reactive aldehydes derived from lipid peroxidation, 4-hydroxynonenal (HNE) is the most abundant endproduct. The concentration of HNE in human serum is 0.05-0.15 μM under physiological conditions (15). However, HNE levels may reach 3-6 μM in tissues under oxidative stress (16,17). Because of its high solubility in aqueous fluids, the reactive HNE formed in membranes can diffuse into the cytoplasm. HNE is detoxified by conjugation to glutathione by glutathione S-transferase (18,19). However, some HNE molecules escape this mechanism and react with the side chains of cysteine, histidine and lysine residues in proteins (20)(21)(22). HNE thus has emerged as an important second messenger signaling molecule (18,19). For example, low concentrations of HNE produce beneficial effects, including the stimulation of endogenous antioxidant defense mechanisms and the inhibition of inflammation (19,(23)(24)(25)(26). Currently, two mechanisms are proposed for HNE-mediated regulation of inflammation. 1) HNE facilitates antioxidant expression by activating Nrf2 signaling, via disrupting Keap1−Nrf2 association and preventing Nrf 2 degradation (24,25,27). Nrf2 stimulates antioxidant expression and increases the resistance to cytotoxic reactive oxygen species (ROS), ther...

Abdominal aortic aneurysm (AAA), commonly occurring in the aged population, is a degenerative disease that dilate and weaken infrarenal aorta due to progressive degeneration of aortic wall integrity. Vinpocetine, a derivative of alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment in the aged population. Recent studies have indicated that vinpocetine antagonizes occlusive vascular disorders such as intimal hyperplasia and atherosclerosis. However, its role in vascular degenerative disease AAA remains unexplored. Herein, we determined the effect of vinpocetine on the formation of AAA as well as the intervention of pre-existing moderate AAA. AAA was induced by periaortic elastase application in C57BL/6J mice. Systemic vinpocetine treatment was applied daily via intraperitoneal injection. We showed that vinpocetine pre-treatment remarkably attenuated aneurysmal dilation assessed by diameter and volume. More importantly, vinpocetine also significantly suppressed the progression of pre-existing moderate AAA in a post-intervention model. Vinpocetine improved multiple cellular and molecular changes associated with AAA, such as elastin degradation, media smooth muscle cell depletion, collagen fibers remodeling and macrophage infiltration in aneurysmal tissues. Vinpocetine potently suppressed TNF-α-induced NF-κB activation and proinflammatory mediator expression in primary cultured macrophages in vitro, as well as in the aorta wall in vivo, suggesting vinpocetine conferred anti-AAA effect at least partially via the inhibition of inflammation. Taken together, our findings reveal a novel role of vinpocetine in AAA formation, development, and progression. Given the excellent safety profile of vinpocetine, this study suggests vinpocetine may be a novel therapeutic agent for AAA prevention and treatment.

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Cyclic nucleotides cAMP and cGMP are important regulators of immune cell functions. Phosphodiesterases (PDEs) hydrolyze cAMP and/or cGMP and, thus, play crucial roles in cyclic nucleotide homeostasis. Abnormal alterations of PDE expression have been implicated in several diseases. To understand the function of PDEs in macrophages, we screened for all PDE genes in both peritoneal and alveolar macrophages from C57BL/6J mice and found that PDE4B and PDE10A are highly induced by LPS. A number of PDE4 inhibitors have been used clinically for the treatment of inflammatory lung diseases. However, the role of PDE10A in inflammation is still poorly understood. We therefore investigated the role of PDE10A in macrophage inflammatory response in vitro and acute lung inflammation in vivo. We found that LPS induces a sustained PDE10A expression in macrophages, which is different from a transient induction by PDE4B. PDE10A inhibition blocked LPS-induced MCP-1 expression, but not TNF-α, whereas PDE4B inhibition blocked LPS-induced TNF-α expression, but not MCP-1. In addition, PDE10A inhibition or deficiency decreased LPS-induced HIF-1α protein expression and subsequently suppressed MCP-1 expression. In vivo, PDE10A expression was also elevated in lung tissue after LPS exposure. Global PDE10A knockout or systemic administration of the PDE10A inhibitor TP-10 in mice significantly suppressed inflammatory molecule levels in the lung tissue and bronchoalveolar lavage fluid as well as inflammatory cell infiltration. These findings show that PDE10A plays a critical role in lung inflammation by promoting the activation of resident macrophages and infiltration of neutrophils.

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