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The Coronavirus Disease 2019 (COVID-19) pandemic has become a global crisis and is more devastating than any other previous infectious disease. It has affected a significant proportion of the global population both physically and mentally, and destroyed businesses and societies. Current evidence suggested that immunopathology may be responsible for COVID-19 pathogenesis, including lymphopenia, neutrophilia, dysregulation of monocytes and macrophages, reduced or delayed type I interferon (IFN-I) response, antibody-dependent enhancement, and especially, cytokine storm (CS). The CS is characterized by hyperproduction of an array of pro-inflammatory cytokines and is closely associated with poor prognosis. These excessively secreted pro-inflammatory cytokines initiate different inflammatory signaling pathways via their receptors on immune and tissue cells, resulting in complicated medical symptoms including fever, capillary leak syndrome, disseminated intravascular coagulation, acute respiratory distress syndrome, and multiorgan failure, ultimately leading to death in the most severe cases. Therefore, it is clinically important to understand the initiation and signaling pathways of CS to develop more effective treatment strategies for COVID-19. Herein, we discuss the latest developments in the immunopathological characteristics of COVID-19 and focus on CS including the current research status of the different cytokines involved. We also discuss the induction, function, downstream signaling, and existing and potential interventions for targeting these cytokines or related signal pathways. We believe that a comprehensive understanding of CS in COVID-19 will help to develop better strategies to effectively control immunopathology in this disease and other infectious and inflammatory diseases.

Hyperoxia plays a key role in the development of bronchopulmonary dysplasia (BPD), a chronic lung disease of preterm infants. This study aimed to investigate the role of NLRP3/caspase-1/gasdermin D (GSDMD)-mediated pyroptosis in hyperoxia-induced lung injury in neonatal mice and to evaluate the potential protective effects of the caspase-1 inhibitor VX-765 on alveolar and vascular development in hyperoxia-exposed lungs. C57/BL6 mouse pups were randomized on postnatal Day 4 (PN4) to receive daily intraperitoneal injections of VX-765, an effective and selective caspase-1 inhibitor, or a vehicle during exposure to room air or hyperoxia (85% O ) for 10 days. Alveolarization was assessed by H&E staining. Pulmonary vascular development was detected by CD31 immunohistochemistry. The degree of fibrosis was analyzed by Masson staining. TUNEL and Ki67 immunofluorescence staining was performed to assess overall cell survival in lung tissue. Concentrations of IL-1β was detected by ELISA in lung homogenates. The expressions of pyroptosis-associated proteins, NLRP3, Caspase-1 p20, N-GSDMD and mature IL-1β were evaluated by Western blot. Immunofluorescence colocalization of F4/80 with NLRP3/Caspase-1/IL-1β was performed. CD68 and AQP5 protein expression was analyzed by immunohistochemistry. Hyperoxia activated the NLRP3 inflammasome, increased the production of mature IL-1β, and upregulated the expression of N-GSDMD, the active form of GSDMD that is responsible for the programmed cell death mechanism of pyroptosis in lung tissue. Importantly, VX-765 decreased NLRP3, IL-1β activation, and N-GSDMD expression and improved alveolar and vascular development by inhibiting pyroptosis of macrophages in hyperoxia-exposed lungs. Moreover, VX-765 also promoted cell proliferation and AT1 survival in the hyperoxia-exposed lung. NLRP3/Caspase-1/GSDMD-mediated pyroptosis plays a critical role in hyperoxia-induced neonatal lung injury, and targeting this pathway may be beneficial for the prevention of lung injury in preterm infants.

N 6 -methyladenosine (m 6 A), the most prevalent mRNA modification, has an important function in diverse biological processes. However, the involvement of m 6 A in allergic asthma and macrophage homeostasis remains largely unknown. Here we show that m 6 A methyltransferases METTL3 is expressed at a low level in monocyte-derived macrophages from childhood allergic asthma patients. Conditional knockout of Mettl3 in myeloid cells enhances Th2 cell response and aggravates allergic airway inflammation by facilitating M2 macrophage activation. Loss and gain functional studies confirm that METTL3 suppresses M2 macrophage activation partly through PI3K/AKT and JAK/STAT6 signaling. Mechanistically, m 6 A-sequencing shows that loss of METTL3 impairs the m 6 A-YTHDF3-dependent degradation of PTX3 mRNA, while higher PTX3 expression positively correlates with asthma severity through promoting M2 macrophage activation. Furthermore, the METTL3/YTHDF3-m 6 A/PTX3 interactions contribute to autophagy maturation in macrophages by modulating STX17 expression. Collectively, this study highlights the function of m 6 A in regulating macrophage homeostasis and identifies potential targets in controlling allergic asthma. The function of METTL3 and RNA methylation is important in various biological processes. Here the authors show that METTL3 is reduced in childhood asthma patients and that conditional knockout of Mettl3 in mouse myeloid cells enhances Th2 response and allergic asthma associated with changes in macrophage function.

The aryl hydrocarbon receptor (AhR) functions in the regulation of intestinal inflammation, but knowledge of the underlying mechanisms in innate immune cells is limited. Here, we investigated the role of AhR in modulating the functions of macrophages in inflammatory bowel disease pathogenesis. The cellular composition of intestinal lamina propria CD45 leukocytes in a dextran sulfate sodium (DSS)-induced mouse colitis model was determined by single-cell RNA sequencing. Macrophage pyroptosis was quantified by analysis of lactate dehydrogenase release, propidium iodide staining, enzyme-linked immunosorbent assay, western blot, and flow cytometry. Differentially expressed genes were confirmed by RNA-seq, RT-qPCR, luciferase assay, chromatin immunoprecipitation, and immunofluorescence staining. AhR deficiency mediated dynamic remodeling of the cellular composition of intestinal lamina propria (LP) CD45 immune cells in a colitis model, with a significant increase in monocyte-macrophage lineage. Mice with AhR deficiency in myeloid cells developed more severe dextran sulfate sodium induced colitis, with concomitant increased macrophage pyroptosis. Dietary supplementation with an AhR pre-ligand, indole-3-carbinol, conferred protection against colitis while protection failed in mice lacking AhR in myeloid cells. Mechanistically, AhR signaling inhibited macrophage pyroptosis by promoting ornithine decarboxylase 1 ( ) transcription, to enhance polyamine biosynthesis. The increased polyamine, particularly spermine, inhibited NLRP3 inflammasome assembly and subsequent pyroptosis by suppressing K efflux. expression was positively correlated with in intestinal mucosal biopsies from patients with ulcerative colitis. These findings suggest a functional role for the AhR/ODC1/polyamine axis in maintaining intestinal homeostasis, providing potential targets for treatment of inflammatory bowel disease.