Infection with SARS-CoV-2, the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic, causes respiratory problems and multifaceted organ dysfunction. A crucial mechanism of COVID-19 immunopathy is the recruitment and activation of neutrophils at the infection site, which also predicts disease severity and poor outcomes. The release of neutrophil extracellular traps (NETs), occurring during a regulated form of neutrophil cell death known as NETosis, is a key effector function that mediates harmful effects caused by neutrophils. Abundant NETosis and NET generation have been observed in the neutrophils of many COVID-19 patients, leading to unfavorable coagulopathy and immunothrombosis. Moreover, excessive NETosis and NET generation are now more widely recognized as mediators of additional pathophysiological abnormalities following SARS-CoV-2 infection. In this minireview, we introduce subtypes of NET-producing neutrophils (e.g., low-density granulocytes) and explain the biological importance of NETs and the protein cargos of NETs in COVID-19. In addition, we discuss the mechanisms by which SARS-CoV-2 causes NETosis by upregulating viral processes (e.g., viral entry and replication) as well as host pro-NET mechanisms (e.g., proinflammatory mediator release, platelet activation, and autoantibody production). Furthermore, we provide an update of the main findings of NETosis and NETs in immunothrombosis and other COVID-19-related disorders, such as aberrant immunity, neurological disorders, and post COVID-19 syndromes including lung fibrosis, neurological disorder, tumor progression, and deteriorated chronic illness. Finally, we address potential prospective COVID-19 treatment strategies that target dysregulated NETosis and NET formation via inhibition of NETosis and promotion of NET degradation, respectively.

Sepsis is a disorder of the immune response to infection or infectious factors with high morbidity and mortality in clinical settings. The lactylation of lysine residues, fueled by lactate, plays a pivotal role in its pathophysiology. In conducting a literature review on sepsis-related research, we employed a systematic approach to ensure comprehensiveness and accuracy. Initially, we conducted an extensive literature search through the PubMed database, utilizing a range of keywords including “sepsis”, “lactate”, “lactylation”, and “epigenetic modification”. The aim was to capture the most recent research related to the pathophysiological mechanisms of sepsis, metabolic disorders, and the role of lactylation. The results of the literature review revealed a close link between sepsis and metabolic dysfunction, particularly the pivotal role of lactylation in regulating immune responses and inflammatory processes. Lactate, not only an energy metabolic byproduct produced during glycolysis, affects the activity of various proteins, including those involved in immune regulation and cell signaling, through lactylation. In the context of sepsis, changes in the levels of lactylation may be closely associated with the severity and prognosis of the disease. In summary, lactylation, as an emerging type of epigenetic modification, provides a new perspective for the diagnosis and treatment of sepsis. Future research needs to further elucidate the exact mechanisms of lactylation in sepsis and explore its potential as a therapeutic target. Plain Language Summary: The annual incidence and mortality rates associated with sepsis are on the rise, and to date, no medications or therapies have been proven effective in clinical practice. Glycolysis plays a pivotal role in regulating lactylation, a process derived from lactate generated by cellular glucose metabolism. In the context of sepsis, elevated lactate levels are indicative of a poor prognosis. It is imperative to delve into the mechanisms underlying lactylation alterations during sepsis to enhance our comprehension of its complex pathophysiology and to pinpoint innovative therapeutic targets for the condition.

Background: The global use of plastic materials has undergone rapid expansion, resulting in the substantial generation of degraded and synthetic microplastics and nanoplastics (MNPs), which have the potential to impose significant environmental burdens and cause harmful effects on living organisms. Despite this, the detrimental impacts of MNPs exposure towards host cells and tissues have not been thoroughly characterized. Results: In the present study, we have elucidated a previously unidentified hepatotoxic effect of 20 nm synthetic polystyrene nanoparticles (PSNPs), rather than larger PS beads, by selectively inducing necroptosis in macrophages. Mechanistically, 20 nm PSNPs were rapidly internalized by macrophages and accumulated in the mitochondria, where they disrupted mitochondrial integrity, leading to heightened production of mitochondrial reactive oxygen species (mtROS). This elevated mtROS generation essentially triggered necroptosis in macrophages, resulting in enhanced crosstalk with hepatocytes, ultimately leading to hepatocyte damage. Additionally, it was demonstrated that PSNPs induced necroptosis and promoted acute liver injury in mice. This harmful effect was significantly mitigated by the administration of a necroptosis inhibitor or systemic depletion of macrophages prior to PSNPs injection. Conclusion: Collectively, our study suggests a profound toxicity of environmental PSNP exposure by triggering macrophage necroptosis, which in turn induces hepatotoxicity via intercellular crosstalk between macrophages and hepatocytes in the hepatic microenvironment.

Background: Alternative (M2)-activated macrophages drive the anti-inflammatory response against sepsis, a leading cause of death in patients suffering from burn injury. Macrophage M2 polarization is intrinsically linked with dominant oxidative phosphorylation (OXPHOS). Glutamine serves as a major anaplerotic source to fuel OXPHOS, but it remains unknown whether glutamine can modulate metabolic checkpoints in OXPHOS that favour M2 polarization. The study aims to explore whether glutamine essentially supports M2 polarization in IL-4-stimulated murine macrophages by sustaining the activity of PDH and whether glutamine augments macrophage M2 polarization and thus alleviates inflammation and organ injury in a murine burn sepsis model.Methods: To understand how glutamine promotes M2 activation in interleukin (IL-4)-treated murine macrophages, we detected glutamine-dependent M2 polarization and its relationship with the pyruvate dehydrogenase (PDH) complex by RT-PCR, flow cytometry and western blot. To explore how glutamine modulates PDH activity and thus supports M2 polarization, we compared the expression, phosphorylation and succinylation status of PDHA1 and then examined sirtuin SIRT5-dependent desuccinylation of PDHA1 and the effects of SIRT5 overexpression on M2 polarization by RT-PCR, flow cytometry and western blot. To determine whether glutamine or its metabolites affect M2 polarization, macrophages were cocultured with metabolic inhibitors, and then SIRT5 expression and M2 phenotype markers were examined by RT-PCR, flow cytometry and western blot. Finally, to confirm the in vivo effect of glutamine, we established a burn sepsis model by injecting Pseudomonas aeruginosa into burn wounds and observing whether glutamine alleviated proinflammatory injuries by RT-PCR, flow cytometry, western blot, immunofluorescent staining, hematoxylin-eosin staining and enzyme-linked immuno sorbent assay.Results: We showed that consumption of glutamine supported M2 activation in IL-4-treated murine macrophages by upregulating the activity of PDH. Mechanistically, glutamine did not affect the expression or alter the phosphorylation status of PDHA1 but instead downregulated the expression of SIRT5 and repressed SIRT5-dependent desuccinylation on PDHA1, which in turn recovered PDH activity and supported M2 polarization. This effect was implemented by its secondary metabolite α-ketoglutarate (αKG) rather than glutamine itself. Finally, we demonstrated that glutamine promoted macrophage M2 polarization in a murine burn sepsis model, thereby repressing excessive inflammation and alleviating organ injury in model mice.Conclusions: Glutamine mitigates murine burn sepsis by essentially supporting macrophage M2 polarization, with a mechanism involving the repression of the SIRT5-mediated desuccinylation of pyruvate dehydrogenase that replenishes OXPHOS and sustains M2 macrophages.

Activation of the NLRP3 inflammasome, which catalyzes maturation of proinflammatory cytokines like IL-1βand IL-18, is implicated and essentially involved in many kinds of inflammatory disorders. Chloroquine (CQ) is a traditional antimalarial drug and also possesses an anti-inflammatory property. In this study, we investigated whether CQ suppresses NLRP3 inflammasome activation and thereby confers protection against murine endotoxic shock. CQ attenuated NF-κB and MAPK activation and prohibited expression of IL-1β, IL-18, andNlrp3in LPS treated murine bone marrow-derived macrophages (BMDMs), demonstrating its inhibitory effect on the priming signal of NLRP3 activation. Then, CQ was shown to inhibit caspase-1 activation and ASC specks formation in BMDMs, which indicates that CQ also suppresses inflammasome assembly, the second signal for NLRP3 inflammasome activation. In a murine endotoxic shock model, CQ effectively improved survival and markedly reduced IL-1βand IL-18 production in serum, peritoneal fluid, and lung tissues. Moreover, CQ reduced protein levels of NLRP3 and caspases-1 p10 in lung homogenates of mice with endotoxic shock, which may possibly explain its anti-inflammatory activity and life protection efficacy in vivo. Overall, our results demonstrate a new role of CQ that facilitates negative regulation on NLRP3 inflammasome, which thereby confers protection against lethal endotoxic shock.