Cervical carcinoma induces NLRP3 inflammasome activation and IL-1ß release in human peripheral blood monocytes affecting patients' overall survival.

PURPOSE: Our group previously demonstrated that genetic variants in inflammasome genes contribute to protection against the establishment of human papilloma virus (HPV)-associated cervical carcinoma (CC). The objective of this study was to better understand the contribution of inflammasome and its cytokines in the CC microenvironment. METHODS: The inflammasome activation was analyzed in CC tumoral cell lines and healthy donors (HD)' monocytes in co-culture. In vitro results were then compared to CC patients' public databases. RESULTS: CC cells did not produce IL-1ß or IL-18 themselves, however, when in co-culture with HD monocytes, induced IL-1ß release in those leucocytes. Inflammasome activation appears to be partially dependent on the NLRP3 receptor. Public data analysis revealed that IL1B expression is increased in the CC compared to normal uterine cervix, and that patients with high IL1B expression had a shorter overall survival. CONCLUSION: CC microenvironment can activate the inflammasome and IL-1ß release in surrounding monocytes, which could be detrimental for CC prognosis.

Common pathogen-associated molecular patterns induce the hyper-activation of NLRP3 inflammasome in circulating B lymphocytes of HIV-infected individuals.

OBJECTIVE: Despite the antiretroviral treatment, people with HIV (PWH) still experience systemic chronic inflammation and immune-senescence, which represent risk factors for severe comorbidities and inefficient response to pathogens and vaccines. Given the dysregulation of NLRP3 inflammasome in PWH and the recently demonstrated role played by NLRP3 in B lymphocytes, we hypothesized that NLRP3 dysregulation in B cells can contribute to chronic inflammation and humoral dysfunction in PWH. DESIGN: NLRP3 inflammasome activation was evaluated in B lymphocytes and correlated with antibodies production and immunization response in PWH. METHODS: NLRP3 inflammasome activation was compared in B lymphocytes isolated from PWH and healthy donors, in resting and stimulated conditions. Functional polymorphic variants in NLRP3 and IL1B genes were analysed in a cohort of PWH submitted to anti-HBV vaccine to assess the effect of NLRP3 inflammasome on humoral response. RESULTS: The NLRP3 inflammasome activation in response to common PAMPs (LPS, ß-glucan) resulted higher in B lymphocytes of PWH than in HD. CpG-induced IgM secretion was also increased in B cells of PWH. NLRP3, but not IL1B, gain-of-function polymorphism associated to anti-HBs levels. CONCLUSION: These data reveal the dysregulation of NLRP3 inflammasome in B lymphocytes of PWH. Differently from myeloid compartment, which present an exhausted NLRP3 inflammasome, the complex appears to be hyper-activated in B cells of PWH, likely contributing to chronic inflammation and affecting humoral response.

Flagellin/NLRC4 Pathway Rescues NLRP3-Inflammasome Defect in Dendritic Cells From HIV-Infected Patients: Perspective for New Adjuvant in Immunocompromised Individuals.

Introduction: NLRP3 inflammasome plays a key role in dendritic cells (DC) activation in response to vaccine adjuvants, however we previously showed that it is not properly activated in DC from HIV-infected patients (HIV-DC), explaining, at least in part, the poor response to immunization of these patients. Taking in account that several cytoplasmic receptors are able to activate inflammasome, and that bacterial components are considered as a novel and efficient adjuvant, we postulated that bacterial flagellin (FLG), a natural ligand of NAIP/NLRC4 inflammasome, could rescue the activation of the complex in HIV-DC. Objective: Demonstrate that FLG is able to activate monocyte-derived dendritic cells from HIV-infected individuals better than LPS, and to what extent the entity of inflammasome activation differs between DC from HIV-infected patients and healthy donors. Methods: Monocyte-derived dendritic cells from HIV-infected patients (HIV-DC) and healthy donors (HD-DC) were stimulated with FLG, and inflammasome as well as DC activation (phenotypic profile, cytokine production, autologous lymphocytes activation) were compared. Chemical and genetic inhibitors were used to depict the relative contribution of NLRC4 and NLRP3 in HIV/HD-DC response to FLG. Results: FLG properly activates HD-DC and HIV-DC. FLG induces higher inflammasome activation than LPS in HIV-DC. FLG acts through NLRC4 and NLRP3 in HD-DC, but at a lesser extent in HIV-DC due to intrinsic NLRP3 defect. Conclusions: FLG by-passes NLRP3 defect in HIV-DC, through the activation of NAIP/NLRC4 inflammasome, indicating possible future use of the bacterial component as an efficient adjuvant in immunocompromised individuals.