The inflammasome is a cytoplasmic multiprotein complex responsible for the activation of inflammatory caspases (caspase-1, -4, and -5) in response to pathogen- and/or damage-associated molecular ...patterns or to homeostasis-altering molecular pathways, and for the consequent release of the pro-inflammatory cytokines interleukin (IL)-1ß and IL-18. Taking in account the complexity of inflammasome activation and that several regulatory steps are involved in maintaining its physiologic role in homeostasis and innate immune response, it does not surprise that several genetic variants in inflammasome components have been associated with common pathologies in the general population, such as autoimmune disorders, cardiovascular diseases, obesity and associated metabolic syndrome, neurodegenerative diseases, and cancer. Moreover, the susceptibility to infectious agents and/or to develop severe complications during infections also has been related to inflammasome genetics. In this work, we revised genetic association studies about polymorphisms of main inflammasome genes in sterile as well as infectious diseases, trying to depict the genetic contribution of inflammasome in disease pathogenesis.
The formation of microthrombi in lung autopsies indicates the involvement of NETs in the immunopathogenesis of severe COVID-19. Therefore, supplements inhibiting NET formation, in association with ...drugs with fewer adverse effects, should be a relevant strategy to attenuate the disease. Resveratrol (RESV) is a natural polyphenol with an important antiviral and antioxidant role. To modulate neutrophils from patients infected with SARS-CoV-2, we evaluated the in vitro effect of RESV on NET formation. Herein, we investigated 190 patients hospitalized with moderate, severe, and critical symptoms at Hospital das Clínicas, Brazil. We observed that neutrophilia in patients with severe COVID-19 infection is composed of neutrophils with activated profile able to release NET spontaneously. Notably, RESV decreased the neutrophil-activated status and the release of free DNA, inhibiting NET formation even under the specific PMA stimulus. At present, there is no evidence of the role of RESV in neutrophils from patients with COVID-19 infection. These findings suggest that adjunctive therapies with RESV may help decrease the inflammation of viral or bacterial infection, improving patient outcomes.
SARS‐CoV‐2 triggers inflammasome‐dependent release of pro‐inflammatory cytokine IL‐1β and pyroptosis, therefore, contributes to the huge inflammatory response observed in severe COVID‐19 patients. ...Less is known about the engagement of inflammasome in neutrophils, main players in tissue injury and severe infection. We studied the activation of the inflammasome in neutrophils from severe COVID‐19 patients and assessed its consequence in term of cells contribution to disease pathogenesis. We demonstrated that NLRP3 inflammasome is dramatically activated in neutrophils from severe COVID‐19 patients and that the specific inhibition of NLRP3 reverts neutrophils' activation. Next, the stimulation of severe patients' neutrophils with common NLRP3 stimuli was not able to further activate the inflammasome, possibly due to exhaustion or increased percentage of circulating immature neutrophils. Collectively, our results demonstrate that the NLRP3 inflammasome is hyperactivated in severe COVID‐19 neutrophils and its exhaustion may be responsible for the increased susceptibility to subsequent (and possibly lethal) infections. Our findings thus include a novel piece in the complex puzzle of COVID‐19 pathogenesis.
Objective and design
The heterogeneity of response to SARS-CoV-2 infection is directly linked to the individual genetic background. Genetic variants of inflammasome-related genes have been pointed as ...risk factors for several inflammatory sterile and infectious disease. In the group of inflammasome receptors, NLRP1 stands out as a good novel candidate as severity factor for COVID-19 disease.
Methods
To address this question, we performed an association study of
NLRP1
,
DPP9
,
CARD8
,
IL1B
, and
IL18
single nucleotide variants (SNVs) in a cohort of 945 COVID-19 patients.
Results
The NLRP1 p.Leu155His in the linker region, target of viral protease, was significantly associated to COVID-19 severity, which could contribute to the excessive cytokine release reported in severe cases.
Conclusion
Inflammasome genetic background contributes to individual response to SARS-CoV-2.
Neutrophil extracellular traps (NETs) are a key antimicrobial feature of cellular innate immunity mediated by polymorphonuclear neutrophils (PMNs). NETs counteract microbes but are also linked to ...inflammation in atherosclerosis, arthritis, or psoriasis by unknown mechanisms. Here, we report that NET-associated RNA (naRNA) stimulates further NET formation in naive PMNs via a unique TLR8-NLRP3 inflammasome-dependent pathway. Keratinocytes respond to naRNA with expression of psoriasis-related genes (e.g., IL17, IL36) via atypical NOD2-RIPK signaling. In vivo, naRNA drives temporary skin inflammation, which is drastically ameliorated by genetic ablation of RNA sensing. Unexpectedly, the naRNA-LL37 'composite damage-associated molecular pattern (DAMP)' is pre-stored in resting neutrophil granules, defining sterile NETs as inflammatory webs that amplify neutrophil activation. However, the activity of the naRNA-LL37 DAMP is transient and hence supposedly self-limiting under physiological conditions. Collectively, upon dysregulated NET release like in psoriasis, naRNA sensing may represent both a potential cause of disease and a new intervention target.
Aim
To assess the effect of aesthetic crown lengthening (ACL) and lip repositioning surgery (LRS) on perception of smile attractiveness.
Materials and methods
Preoperative and 6‐month postoperative ...smile photographs of ACL‐ or LRS‐treated patients were evaluated by 100 raters (five gender‐balanced groups of ten per procedure) of diverse background (dental students, general dentists, periodontists and laypersons with and without any aesthetic concerns about their own smile). Smile attractiveness was rated by visual analogue scale (VAS). Multivariate mixed‐effect models were applied to determine the effect of procedure, rater (age, gender and group) and case (gingival display and GD) on smile attractiveness rating.
Results
Average preoperative and postoperative VAS scores for ACL patients were 3.8 ± 2.0 and 6.2 ± 1.9, respectively. Corresponding LRS patient values were 4.8 ± 2.0 and 6.4 ± 1.9. Treatment, baseline GD and rater age were significant determinants (p < .001) of smile attractiveness for both procedures. Rater gender was not significant. Rater group was significant (p < .032) only for ACL. Procedure (p < .001), baseline VAS (p < .001), change in GD (p ≤ .002) and rater age (p ≤ .017) were significant determinants of smile attractiveness change from preoperative to postoperative.
Conclusions
ACL and LRS are two periodontal plastic surgery procedures that deliver significant smile attractiveness improvements, in the eyes of both laypersons and dental professionals.
Host genetics affects both susceptibility and progression of HIV-1 infection. NLRP3 inflammasome provides a first-line defense in viral infections, and, accordingly, gain-of-function variants in ...NLRP3 have been associated with protection against HIV-1.
Despite antiretroviral treatment (ART), HIV-infected patients continue to present systemic inflammation with a heterogeneous prognosis. As NLRP3 inflammasome is involved in several chronic diseases by amplifying “sterile” inflammation, its role in chronic phase of HIV infection has been postulated.
Little is known about inflammasome genetics in HIV-infected patients and whether it may play a role in the different clinical outcomes. Therefore, we questioned whether NLRP3 inflammasome genetics could affect the clinical course of HIV-1 infection as it does in host/virus interaction.
For this purpose, we analyzed selected single nucleotide polymorphisms (SNPs) in ART-treated HIV-infected patients (n = 300), in Long Term Non-Progressors/Elite Controllers and progressors (n = 133), and in HIV-infected individuals submitted to dendritic cell (DC)-based immunotherapy (n = 19).
SNPs leading to increased activation of NLRP3 inflammasome are beneficial for patients, while SNPs that negatively affect NLRP3 activation or IL-18 production, detrimental. In contrast, gain-of-function variant in IL1B is also detrimental for patients, suggesting that while IL-1ß possible contributes to immune exhaustion, the axis NLRP3-inflammasome/IL-18 could act positively in chronic infection. Functional assays supported genetic results: NLRP3 variants associated with good quality HIV+ DC, and IL1B -511C > T with a poor one. Loss-of-function SNPs affect HIV+ T cells proliferation.
These findings proposed for the first time that NLRP3 inflammasome, mainly through IL-18, play a protective role in chronic HIV infection.
The interplay between
(Mtb) and humans is multifactorial. The susceptibility/resistance profile and the establishment of clinical tuberculosis (TB) still remains elusive. The gain-of-function variant ...rs10754558 in the
gene (found in 30% of the world population) confers protection against the development of TB, indicating a prominent role played by NLRP3 inflammasome against Mtb. Through genotype-guided assays and various Mtb strains (BCG, H37Rv, Beijing-1471, MP287/03), we demonstrate that Mtb strains activate inflammasome according to the NLRP3/IL-1ß or NLRC4/IL18 preferential axis.
and
enetic variants contribute to the presentation of TB. For the first time, we have shown that loss-of-function variants in
significantly contribute to the development of extra-pulmonary TB. The analysis of inflammasome activation in a cohort of TB patients and their "household contacts" (CNT) revealed that plasma IL-1ß/IFN-α ratio lets us distinguish patients from Mtb-exposed-but-healthy individuals from an endemic region. Moreover, NLRP3 inflammasome seemed "exhausted" in TB patients compared to CNT, indicating a more efficient activation of inflammasome in resistant individuals. These findings suggest that inflammasome genetics as well as virulence-dependent level of inflammasome activation contribute to the onset of a susceptible/resistant profile among Mtb-exposed individuals.
Placental malaria (PM) is associated with severe inflammation leading to abortion, preterm delivery, and intrauterine growth restriction. Innate immunity responses play critical roles, but the ...mechanisms underlying placental immunopathology are still unclear. Here, we investigated the role of inflammasome activation in PM by scrutinizing human placenta samples from an endemic area and ablating inflammasome components in a PM mouse model. The reduction in birth weight in babies from infected mothers is paralleled by increased placental expression of AIM2 and NLRP3 inflammasomes. Using genetic dissection, we reveal that inflammasome activation pathways are involved in the production and detrimental action of interleukin-1β (IL-1β) in the infected placenta. The IL-1R pharmacological antagonist Anakinra improved pregnancy outcomes by restoring fetal growth and reducing resorption in an experimental model. These findings unveil that IL-1β-mediated signaling is a determinant of PM pathogenesis, suggesting that IL-1R antagonists can improve clinical outcomes of malaria infection in pregnancy.
PDF
