Abstract P123: Obesity-Related Inflammasome Activation in COVID-19 and Chronic Conditions: A Post-Mortem Lung Biopsies Study

Abstract

Background: Obesity has been identified as an independent risk factor for severe COVID-19 outcomes. The association between viral infections and obesity, observed previously, suggests that obese individuals are more prone to severe complications. Several factors, such as increased ACE2 receptor expression, anatomical effects on lung function, and chronic inflammation contribute to this relationship yet the activation of the NLRP3 inflammasome pathway is a key element in understanding this mechanism. Objective: This study, conducted with post-mortem lung biopsies of obese individuals who died from COVID-19 (Group A) and from chronic conditions (Group B), focused on the involvement of the NLRP3 inflammasome pathway. Our primary goal was to determine whether chronic NLRP3 inflammasome activation in obese individuals is different in critical COVID-19 and in critical chronic conditions. Methodology: We conducted a retrospective analysis utilizing clinical data and post-mortem lung tissue samples from two distinct groups. Group A comprised 14 obese patients who succumbed to COVID-19, while Group B consisted of 9 obese individuals who passed away from causes unrelated to COVID-19, including thromboembolic events, metastatic neoplasms and acute myocardial infarction. The average age of the groups A and B is, respectively, 67 (ranging from 51 to 86) and 62.6 (ranging from 42 to 79) years. Immunohistochemical analysis was employed to assess the expression of twelve markers associated with inflammation (IL-6, IL-8, TNF-α, IL-18, IL-1β and HIF 1-α.) and the NLRP3 inflammasome pathway (NLRP3, ASC, CASP-1, CASP-9, gasdermin-D). Statistical analysis was performed using Mann-Whitney, Student’s t-test and Fischer’s exact test. Results: Group B showed significantly higher expression of IL-6 (p <0.0001), NLRP3 (p = 0.0004), IL-18 (p = 0.002), HIF 1-α (p = 0.0327), CASP-9 (p < 0.0001), and NF-Kb (p < 0.0001). No significant differences were found for IL-8 (p = 0.8291), TNF-α (p = 0.2349), IL-1β (p = 0.5856), gasdermin-D (p = 0.3301), and ASC (p = 0.0572). CASP-1 expression was higher in Group A (p = 0.0142) marking pyroptosis in the COVID-19 group. Conclusion: While our study did not confirm chronic NLRP3 inflammasome activation was different between the two obese groups, it did reveal a distinctive pattern of cell death through pyroptosis, prevalent in obese individuals with COVID-19. Our findings underscore the necessity for additional research to unveil obesity as the underlying mechanism governing disease severity in infectious diseases.