A 360° view of the inflammasome: Mechanisms of activation, cell death, and diseases.

Inflammasomes are critical sentinels of the innate immune system that respond to threats to the host through recognition of distinct molecules, known as pathogen- or damage-associated molecular patterns (PAMPs/DAMPs), or disruptions of cellular homeostasis, referred to as homeostasis-altering molecular processes (HAMPs) or effector-triggered immunity (ETI). Several distinct proteins nucleate inflammasomes, including NLRP1, CARD8, NLRP3, NLRP6, NLRC4/NAIP, AIM2, pyrin, and caspases-4/-5/-11. This diverse array of sensors strengthens the inflammasome response through redundancy and plasticity. Here, we present an overview of these pathways, outlining the mechanisms of inflammasome formation, subcellular regulation, and pyroptosis, and discuss the wide-reaching effects of inflammasomes in human disease.

AIM2 in regulatory T cells restrains autoimmune diseases.

The inflammasome initiates innate defence and inflammatory responses by activating caspase-1 and pyroptotic cell death in myeloid cells1,2. It consists of an innate immune receptor/sensor, pro-caspase-1, and a common adaptor molecule, ASC. Consistent with their pro-inflammatory function, caspase-1, ASC and the inflammasome component NLRP3 exacerbate autoimmunity during experimental autoimmune encephalomyelitis by enhancing the secretion of IL-1ß and IL-18 in myeloid cells3-6. Here we show that the DNA-binding inflammasome receptor AIM27-10 has a T cell-intrinsic and inflammasome-independent role in the function of T regulatory (Treg) cells. AIM2 is highly expressed by both human and mouse Treg cells, is induced by TGFß, and its promoter is occupied by transcription factors that are associated with Treg cells such as RUNX1, ETS1, BCL11B and CREB. RNA sequencing, biochemical and metabolic analyses demonstrated that AIM2 attenuates AKT phosphorylation, mTOR and MYC signalling, and glycolysis, but promotes oxidative phosphorylation of lipids in Treg cells. Mechanistically, AIM2 interacts with the RACK1-PP2A phosphatase complex to restrain AKT phosphorylation. Lineage-tracing analysis demonstrates that AIM2 promotes the stability of Treg cells during inflammation. Although AIM2 is generally accepted as an inflammasome effector in myeloid cells, our results demonstrate a T cell-intrinsic role of AIM2 in restraining autoimmunity by reducing AKT-mTOR signalling and altering immune metabolism to enhance the stability of Treg cells.

Relationship between fruit and vegetable consumption and internet addiction with insomnia and depression as multiple mediators during the COVID-19 pandemic: a three-wave longitudinal study in Chinese college students.

BACKGROUND: The relationships between fruit and vegetable consumption (FV) and Internet addiction (IA) in college students still remained unknown together with the internal mechanisms. Given the limitations of previous cross-sectional design, longitudinal research was necessary to be conducted to explore more precise correlations. Using the three-wave data in a longitudinal design, this study aimed to explore the association between FV and IA among Chinese college students and potential multiple mediators of insomnia and depression during the COVID-19 pandemic. METHODS: A total of 579 college students were recruited during three waves (T1: August 2020; T2: November 2020; T3: February 2021). FV (T1), insomnia (T2), depression (T2) and IA (T3) symptoms were reported. The descriptive statistics of the sociodemographic characteristics and correlation analyses of the study variables were calculated. The significance of the mediation effects was measured conducting a bootstrap method with SPSS PROCESS macro. RESULTS: FV was negatively correlated with IA, and lower FV predicted higher risk of IA. Depression mediated the association between FV and subsequent IA. Insomnia and depression were multiple mediators, which in turn mediated the links between FV and subsequent IA. CONCLUSIONS: The three-wave longitudinal study has revealed that FV had indirect effects on IA through individual mediating factor of depression and multiple mediating roles of insomnia and depression sequentially. The policy makers, educators and researchers should pay attention to the impact of the interventions from healthy diet, in order to optimize the coping strategies for preventing college students from IA.

Exploring symptom-level associations between anxiety and depression across developmental stages of adolescence: a network analysis approach.

BACKGROUND: Anxiety and depression often co-occur during adolescence, but the associations between symptoms of these two disorders in this developmental period are not yet fully understood. Network analysis provides a valuable approach to uncover meaningful associations among symptoms and offers insights for prevention and intervention strategies. This study aimed to investigate symptom-level associations between anxiety and depression using network analysis and to identify core symptoms, bridge symptoms, and differences in network structure across different stages of adolescence. METHODS: The cross-sectional study was conducted in March 2022 in Shenzhen, China. Participants completed the Generalized Anxiety Disorder Scale-7 and Patient Health Questionnaire Depression Scale, along with demographic questionnaires assessing age and gender. Chinese adolescents aged 10 to 17 who were in Grades 5 or 6 of elementary school, Grades 1 or 2 of middle school, or Grades 1 or 2 of high school, and who could comprehensively understand and read Chinese were recruited as participants. Students in Grade 3 of middle and high schools were excluded due to their upcoming high school or college entrance examinations. Based on age, participants were categorized into early, middle, and late developmental stages of adolescence. RESULTS: "Loss of control" was among the most central symptoms in the comorbidity network throughout all three developmental stages; "excessive worry" and "anhedonia" emerged as the core symptoms in early adolescence, and "restlessness" as the core symptom in late adolescence. "Anhedonia," "sad mood," and "fatigue" were identified as bridge symptoms between anxiety and depression across all three developmental stages of adolescence. The global strength of the network in middle adolescence was significantly higher compared to the other two stages. CONCLUSION: These findings highlight the core and bridge symptoms that require special attention and intervention at each stage of adolescence. Moreover, significantly higher network connectivity in middle adolescence suggests this is a critical period for intervention to prevent the development of comorbid mental disorders.

The Longitudinal Features of Depressive Symptoms During the COVID-19 Pandemic Among Chinese College Students: A Network Perspective.

There is substantial evidence that the Corona Virus Disease 2019 (COVID-19) pandemic increased the risk of depressive symptoms among college students, but the long-term features of depressive symptoms on a symptom level have been poorly described. The current study investigated interaction patterns between depressive symptoms via network analysis. In this longitudinal study, participants included 860 Chinese college students (65.8% female; Mage = 20.6, SDage = 1.8, range: 17-27) who completed a questionnaire at three-time points three months apart. Results demonstrated that fatigue was the most influential symptom, and the occurrence of fatigue could give rise to other depressive symptoms. In addition to predicting other symptoms, fatigue could be predicted by other symptoms in the measurement. The network structures were similar across time, suggesting that the overall interaction pattern of depressive symptoms was stable over the longitudinal course. These findings suggest that depressive symptoms during the COVID-19 period are associated with the presence of fatigue.

Optimal movement behaviors: correlates and associations with anxiety symptoms among Chinese university students.

BACKGROUND: The Canadian 24-Hour Movement Guidelines for Adults was released in 2020. There is a dearth of evidence on the association between adherence to the 24 h movement guidelines and health indicators. This study aims to (a) explore the associations between potential correlates and meeting the 24 h movement guidelines using a sample of Chinese university students; and (b) examine if meeting 24 h movement guidelines is associated with the severity of anxiety symptoms. METHODS: Cross-sectional findings are based on 1846 Chinese university students (mean age = 20.7 years, 64.0% female). Movement behaviors (physical activity, sedentary behavior, and sleep duration), possible correlates, and anxiety symptoms were measured through self-reported online questionnaires. Logistic regression models were performed to examine the associations. RESULTS: We found that male students and those who had a mother with a master's degree or above, more close friends and higher perceived family affluence were more likely to meet the overall 24 h guidelines. Meeting all 24 h movement guidelines presented the lower odds for severe anxiety symptoms than those meeting fewer recommendations in the 24 h movement guidelines. CONCLUSIONS: As one of the first to examine the correlates of adherence to the 24 h movement guidelines and the relationship between anxiety symptoms and meeting the guidelines among Chinese university students, our findings contribute to the growing body of evidence linking movement behaviors, psychosocial correlates, and heath indicators. Schools and health providers can encourage movement behaviors that follow the guidelines on campus.

Dynamic Protein-Metal Ion Networks: A Unique Approach to Injectable and Self-Healable Metal Sulfide/Protein Hybrid Hydrogels with High Photothermal Efficiency.

A new strategy is proposed to fabricate adaptable protein-based hydrogel networks with both injectable and self-healable properties. By mixing proteins and metal ions under alkaline conditions, the metal ions can crosslink proteins into protein-metal ion dynamic networks. Subsequently, the metal ions can react with the cysteine residues of protein to in situ form corresponding metal sulfide NPs with ultra-small size, which leads to nanocomposite hydrogels with adaptable structures. This approach is general and a series of metal sulfide NP in situ embedded nanocomposite hydrogels were obtained. As an example, a Bi2 S3 -BSA hydrogel with tunable networks is shown to serve as an injectable, self-healable photothermal agent for the treatment of tumors. Our finding paves a new avenue for the preparation of injectable and self-healable hydrogels with potential applications in biomedicine.

Association between sports participation and resilience in school-attending students: a cross-sectional study.

Aim: This research sought to identify the association between sports participation and resilience in children and adolescents as a means to enhance mental health. Methods: A comprehensive survey was carried out, encompassing primary, middle, and high school students from chosen educational institutions. The analytical sample comprised 67,281 students of school age. Sports participation and resilience were evaluated using validated assessment tools, while relevant covariates, such as sex and school grade, were assessed through self-reported questionnaires. Generalized Linear Models were applied to ascertain the association between sports participation and resilience for the entire sample, and separately for subgroups divided by gender or school grade, after controlling for covariates. Results: Among the 67,281 school students, males constituted 51.9% of the sample. Approximately 47.1% of the entire sample reported no sports participation, and the average resilience score was 24.7. The regression model analysis revealed that, in the entire sample, increased in sports participation was linked to higher resilience scores (odds ratio [OR] for 1-3 times per month: 1.20, 95%CI: 1.16-1.24; OR for 1-2 times per week: 1.38, 95%CI: 1.33-1.43; OR for 3 times or more per week: 1.72, 95%CI: 1.65-1.79). Analyses stratified by gender and school grade indicated that sports participation was consistently associated with greater resilience. Conclusion: This study provides cross-sectional evidence supporting the positive association between sports participation and the resilience of children and adolescents, underscoring the potential of encouraging sports participation as a strategy for promoting mental health resilience. The findings presented herein should be subject to further confirmation or refutation in future research endeavors.

Objective assessment of the association between telomere length, a biomarker of aging, and health screening indicators: A cross-sectional study.

Physical examination data are used to indicate individual health status and organ health, and understanding which physical examination data are indicative of physiological aging is critical for health management and early intervention. There is a lack of research on physical examination data and telomere length. Therefore, the present study analyzed the association between blood telomere length and physical examination indices in healthy people of different ages to investigate the role and association of various organs/systems with physiological aging in the human body. The present study was a cross-sectional study. Sixteen physical examination indicators of different tissue and organ health status were selected and analyzed for trends in relation to actual age and telomere length (TL). The study included 632 individuals with a total of 11,766 data for 16 physical examination indicators. Age was linearly correlated with 11 indicators. Interestingly, telomere length was strongly correlated only with the renal indicators eGFR (P < .001), CYS-C (P < .001), and SCR (P < .001). The study established that renal aging or injury is a risk factor for Physical aging of the human body. Early identification and management are essential to healthcare.

Quasi-Static Modeling Framework for Soft Bellow-Based Biomimetic Actuators.

Soft robots that incorporate elastomeric matrices and flexible materials have gained attention for their unique capabilities, surpassing those of rigid robots, with increased degrees of freedom and movement. Research has highlighted the adaptability, agility, and sensitivity of soft robotic actuators in various applications, including industrial grippers, locomotive robots, wearable assistive devices, and more. It has been demonstrated that bellow-shaped actuators exhibit greater efficiency compared to uniformly shaped fiber-reinforced actuators as they require less input pressure to achieve a comparable range of motion (ROM). Nevertheless, the mathematical quantification of the performance of bellow-based soft fluidic actuators is not well established due to their inherent non-uniform and complex structure, particularly when compared to fiber-reinforced actuators. Furthermore, the design of bellow dimensions is mostly based on intuition without standardized guidance and criteria. This article presents a comprehensive description of the quasi-static analytical modeling process used to analyze bellow-based soft actuators with linear extension. The results of the models are validated through finite element method (FEM) simulations and experimental testing, considering elongation in free space under fluidic pressurization. This study facilitates the determination of optimal geometrical parameters for bellow-based actuators, allowing for effective biomimetic robot design optimization and performance prediction.

Predicting Hematoma Expansion and Prognosis in Cerebral Contusions: A Radiomics-Clinical Approach.

Hemorrhagic progression of contusion (HPC) often occurs early in cerebral contusions (CC) patients, significantly impacting their prognosis. It is vital to promptly assess HPC and predict outcomes for effective tailored interventions, thereby enhancing prognosis in CC patients. We utilized the Attention-3DUNet neural network to semi-automatically segment hematomas from computed tomography (CT) images of 452 CC patients, incorporating 695 hematomas. Subsequently, 1502 radiomic features were extracted from 358 hematomas in 261 patients. After a selection process, these features were used to calculate the radiomic signature (Radscore). The Radscore, along with clinical features such as medical history, physical examinations, laboratory results, and radiological findings, was employed to develop predictive models. For prognosis (discharge Glasgow Outcome Scale score), radiomic features of each hematoma were augmented and fused for correlation. We employed various machine learning methodologies to create both a combined model, integrating radiomics and clinical features, and a clinical-only model. Nomograms based on logistic regression were constructed to visually represent the predictive procedure, and external validation was performed on 170 patients from three additional centers. The results showed that for HPC, the combined model, incorporating hemoglobin levels, Rotterdam CT score of 3, multi-hematoma fuzzy sign, concurrent subdural hemorrhage, international normalized ratio, and Radscore, achieved area under the receiver operating characteristic curve (AUC) values of 0.848 and 0.836 in the test and external validation cohorts, respectively. The clinical model predicting prognosis, utilizing age, Abbreviated Injury Scale for the head, Glasgow Coma Scale Motor component, Glasgow Coma Scale Verbal component, albumin, and Radscore, attained AUC values of 0.846 and 0.803 in the test and external validation cohorts, respectively. Selected radiomic features indicated that irregularly shaped and highly heterogeneous hematomas increased the likelihood of HPC, while larger weighted axial lengths and lower densities of hematomas were associated with a higher risk of poor prognosis. Predictive models that combine radiomic and clinical features exhibit robust performance in forecasting HPC and the risk of poor prognosis in CC patients. Radiomic features complement clinical features in predicting HPC, although their ability to enhance the predictive accuracy of the clinical model for adverse prognosis is limited.

Differential Associations Between Meeting 24-Hour Movement Guidelines With Mental Wellbeing and Mental Illness Among Chinese Adolescents.

PURPOSE: Contemporary mental health models simultaneously consider psychological distress and wellness. Researchers have proposed that adhering to the 24-hour movement guidelines (24-HMG) contributes to mental health. 24-HMG integrates recommendations of time distribution among sleep, screen use, and moderate to vigorous physical activity (MVPA). Yet, there are few studies on the relationship between meeting 24-HMG and mental health, especially mental wellbeing. This study aimed to examine the associations between adherence to 24-HMG with mental wellbeing and mental illness among Chinese adolescents. METHODS: Cross-sectional data of 67,281 Chinese adolescents aged 10-17 years (mean age = 13.0 years, 51.9% males) were collected by sending online questionnaires to local primary and middle schools in Shenzhen in 2021. We used multilevel generalized linear models to analyze associations between meeting 24-HMG with mental wellbeing (subjective wellbeing, resilience, and positive youth development) and mental illness (depression and anxiety). RESULTS: Only 1.7% of participants met recommendations for all three behaviors (sleep, screen use, and MVPA). Compared with meeting none of the recommendations, participants who met one or more recommendations reported significantly better performance in mental wellbeing (all p < .001); on the contrary, meeting one or more recommendations (except for only meeting the MVPA recommendation) were significantly related to lower severity of mental illness (all p < .001). The relationship between the number of recommendations met with mental well-being and mental illness indicators presented a dose-response pattern (all p < .001). DISCUSSION: Meeting 24-HMG was associated with superior mental health, including a higher propensity for mental wellbeing and a lower risk of mental illness. The importance of limiting screen time and getting enough sleep should be highlighted in promoting mental health in adolescents.

Unhealthy Eating Habits and Insomnia Symptoms are Associated with Internet Addiction in Chinese Left-Behind Children: The Gender Difference.

Purpose: This study aimed to evaluate the associations between unhealthy eating habits and insomnia symptoms with Internet addiction (IA) among Chinese left-behind children (LBC) based on potential gender difference. Methods: This cross-sectional study was conducted in junior high schools from an economically disadvantaged area of China in May 2020. Participants were asked to complete the information and scales of socio-demographic characteristics, eating habits (the frequency of eating carbohydrates, fruits, vegetables, protein, and breakfast), insomnia severity and IA. A total of 3156 LBCs (43.9% males and 56.1% females, aged 14.2 years in average) were used for final analyses. Associations between eating habits and insomnia symptoms with IA were analyzed by generalized linear model with binary logistic regression. Results: The study found that left-behind children (LBCs) had unhealthy eating habits, particularly among females. Females reported more insomnia symptoms than males. The prevalence of IA was similar across genders. Consuming fewer fruits and vegetables and skipping breakfast were linked to increased IA risk, especially in females. Insomnia was significantly associated with higher IA risk in both genders. Conclusion: In LBCs, unhealthy eating and sleep were notably linked to IA, especially in females. Addressing these factors might reduce the prevalence of IA among LBCs.

Eating habits matter for sleep difficulties in children and adolescents: A cross-sectional study.

Background: Sleep difficulties are a common sleep-related problem among children and adolescents. However, the association between eating habits and sleep difficulties has not been extensively studied. Therefore, this study aimed to investigate the relationship between eating habits and sleep difficulties in children and adolescents. Methods: This study utilized cross-sectional data from the 2013/2014 Health Behaviour in School-aged Children survey. A total of 213,879 young adolescents provided self-reported information on their weekday and weekend breakfast consumption, fruit and vegetable intake, sweet and soft drink consumption, and sleep difficulties. Covariates such as sex, age, family affluence, physical activity, and body mass index were also assessed. Multilevel generalized linear modelling was used to analyse the association between independent and dependent. Results were reported as odds ratios (OR) with 95% confidence intervals. Results: Of all study participants, approximately 50% were girls. Regression models indicated that more frequent breakfast consumption was associated with fewer sleep difficulties (e.g., consuming breakfast on weekdays for 5 days: OR = 1.49, 95% CI: 1.45-1.54). Fruit and vegetable consumption once a week or more was also linked to fewer sleep difficulties (all OR > 1.08, ≥ 1.07). In addition, consuming fewer sweets and soft drinks was generally associated with fewer sleep difficulties. Conclusion: This study provides evidence supporting the association between healthier eating habits and reduced sleep difficulties in children and adolescents. Future research using longitudinal or experimental designs is encouraged to confirm or negate these findings. Additionally, this study offers practical guidance for nutritional counselling professionals and sleep health promotion practitioners.

Association Between 24-Hour Movement Guideline and Physical, Verbal, and Relational Forms of Bullying Among Chinese Adolescents.

The Canadian 24-Hour Movement Guidelines for Children and Youth recommends specific guidance in physical activity, screen time, and sleep duration. The current research will further explore potential exposures between healthy movement and being involved in a bullying incident as a bully or a victim in a representative sample of adolescents in China. A total of 67 821 Chinese students (response rate = 98.4%) were included in this study (mean age = 13.04 years). The results showed that meeting sleep recommendation only, meeting screen time recommendation only, and meeting both these two recommendations might be protective factors against being bullied or bullying others. Meeting moderate-to-vigorous physical activity (MVPA) recommendation only reported higher odds of being victims in all forms of bullying while meeting both MVPA and another combination of the guideline would relate to lower odds of being a bully and a bully-victim in all forms of bullying involvement.

A new PHQ-2 for Chinese adolescents: identifying core items of the PHQ-9 by network analysis.

BACKGROUND: The importance of preventing and treating adolescent depression has been gradually recognized in Chinese society, especially in the context of the COVID-19 pandemic. Early screening is the first step. The Patient Health Questionnaire-9 (PHQ-9) is a leading scale in the field of depression screening. To improve screening efficiency in large-scale screening, an even shorten scale is desirable. The PHQ-2, which only included two items measuring anhedonia and depressed mood, is an ultra-form of the PHQ-9. However, emerging evidence suggests that there may be a better short form for the PHQ-9, especially for adolescents. Therefore, using two large samples of Chinese adolescents, this study aimed to identify the core items of the PHQ-9 and examine the short form consisting of core items. METHODS: Surveys were conducted among primary and middle school students in two Chinese cities with different economic levels during the COVID-19 pandemic. Two gender-balanced samples aged 10 to 17 (nSample 1 = 67281, nSample 2 = 16726) were collected. Network analysis was used to identify the core items of the PHQ-9, which were extracted to combine a short version. Reliability, concurrent validity, and the receiver operating characteristic curve (ROC) of the short form were examined. Analyses were gender-stratified. RESULTS: Network analysis identified fatigue and depressed mood as core items in the PHQ-9 among Chinese adolescents. Items measuring Fatigue and Mood were combined to be a new PHQ-2 (PHQ-2 N). The PHQ-2 N displayed satisfactory internal consistency and current validity. Taking the PHQ-9 as a reference, the PHQ-2 N showed higher ROC areas and better sensitivity and specificity than the PHQ-2. The optimal cutoff score for the PHQ-2 N was 2 or 3. CONCLUSIONS: Fatigue and depressed mood are the central symptoms of the depressive symptom network. The PHQ-2 N has satisfactory psychometric properties and can be used in rapid depression screening among Chinese adolescents.

Changes in the networks of complex posttraumatic stress disorder symptoms among Chinese college students with childhood trauma.

OBJECTIVE: To advance understanding of the development of complex posttraumatic stress disorder (CPTSD) symptoms longitudinally and facilitate future treatments, the present study investigated changes in the network of CPTSD symptoms among Chinese college students with childhood trauma. METHOD: A longitudinal study was conducted with college students, following them three times at 3-month intervals. CPTSD symptoms were measured using the International Trauma Questionnaire, and childhood trauma was assessed by the revised Adverse Childhood Experiences Scale. The final sample consisted of 294 participants with childhood trauma at baseline measurement (28.9% were males, Mage = 20.76 years). Comparisons of cross-sectional networks and cross-lagged panel network (CLPN) analysis were performed to characterize the features and changes of interactions among CPTSD symptoms. RESULTS: Sense of failure and isolation were the core symptoms in the cross-sectional networks of CPTSD symptoms. The comparison of cross-sectional networks indicated that the global network strength was stable, and no node's strength centrality and only one edge weight changed significantly from Time 1 (T1) to Time 3 (T3). The findings of the CLPN model reveal that worthlessness, difficulties with intimacy, and flashbacks have the highest out-expected influence. In the T1-T3 network, the strongest edge was from worthlessness to sense of failure. CONCLUSIONS: Cross-sectional network analyses and comparisons revealed the characteristics of CPTSD networks at multiple time points, while the CLPN analysis identified the longitudinal dynamics of CPTSD symptoms. These provide insights for designing more targeted intervention plans for college students with childhood trauma. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Optineurin regulates NRF2-mediated antioxidant response in a mouse model of Paget's disease of bone.

Degenerative diseases affecting the nervous and skeletal systems affect the health of millions of elderly people. Optineurin (OPTN) has been associated with numerous neurodegenerative diseases and Paget's disease of bone (PDB), a degenerative bone disease initiated by hyperactive osteoclastogenesis. In this study, we found age-related increase in OPTN and nuclear factor E2-related factor 2 (NRF2) in vivo. At the molecular level, OPTN could directly interact with both NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) for up-regulating antioxidant response. At the cellular level, deletion of OPTN resulted in increased intracellular reactive oxygen species and increased osteoclastogenic potential. At the tissue level, deletion of OPTN resulted in substantially increased oxidative stress derived from leukocytes that further stimulate osteoclastogenesis. Last, curcumin attenuated hyperactive osteoclastogenesis induced by OPTN deficiency in aged mice. Collectively, our findings reveal an OPTN-NRF2 axis maintaining bone homeostasis and suggest that antioxidants have therapeutic potential for PDB.

An epithelial-immune circuit amplifies inflammasome and IL-6 responses to SARS-CoV-2.

Elevated levels of cytokines IL-1ß and IL-6 are associated with severe COVID-19. Investigating the underlying mechanisms, we find that while primary human airway epithelia (HAE) have functional inflammasomes and support SARS-CoV-2 replication, they are not the source of IL-1ß released upon infection. In leukocytes, the SARS-CoV-2 E protein upregulates inflammasome gene transcription via TLR2 to prime, but not activate, inflammasomes. SARS-CoV-2-infected HAE supply a second signal, which includes genomic and mitochondrial DNA, to stimulate leukocyte IL-1ß release. Nuclease treatment, STING, and caspase-1 inhibition but not NLRP3 inhibition blocked leukocyte IL-1ß release. After release, IL-1ß stimulates IL-6 secretion from HAE. Therefore, infection alone does not increase IL-1ß secretion by either cell type. Rather, bi-directional interactions between the SARS-CoV-2-infected epithelium and immune bystanders stimulates both IL-1ß and IL-6, creating a pro-inflammatory cytokine circuit. Consistent with these observations, patient autopsy lungs show elevated myeloid inflammasome gene signatures in severe COVID-19.