NLRP3 inflammasome activation and its inhibitory drugs in connection with COVID-19 infection
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ABSTRACT:
SUBMITTER: Zafar-Mohammadi K
PROVIDER: S-EPMC9515760 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
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Project description:Severe coronavirus disease 2019 (COVID-19) is characterized by respiratory failure, shock or multiorgan dysfunction, often accompanied by systemic hyperinflammation and dysregulated cytokine release. These features are linked to the intense and rapid stimulation of the innate immune response. The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is a central player in inflammatory macrophage activation which via caspase-1 activation leads to the release of the mature forms of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and via cleavage of Gasdermin D pyroptosis, an inflammatory form of cell death. Here, we discuss the role of NLRP3 activation in COVID-19 and clinical trials currently underway to target NLRP3 to treat severe COVID-19.
| S-EPMC10382191 | biostudies-literature
Project description:Rationale: Stimulation of the NLRP3 inflammasome by metabolic byproducts is known to result in inflammatory responses and metabolic diseases. However, how the host controls aberrant NLRP3 inflammasome activation remains unclear. PPARγ, a known regulator of energy metabolism, plays an anti-inflammatory role through the inhibition of NF-κB activation and additionally attenuates NLRP3-dependent IL-1β and IL-18 production. Therefore, we hypothesized that PPARγ serves as an endogenous modulator that attenuates NLRP3 inflammasome activation in macrophages. Methods: Mouse peritoneal macrophages with exposure to a PPARγ agonist at different stages and the NLRP3 inflammasome-reconstituted system in HEK293T cells were used to investigate the additional anti-inflammatory effect of PPARγ on NLRP3 inflammasome regulation. Circulating mononuclear cells of obese patients with weight-loss surgery were used to identify the in vivo correlation between PPARγ and the NLRP3 inflammasome. Results: Exposure to the PPARγ agonist, rosiglitazone, during the second signal of NLRP3 inflammasome activation attenuated caspase-1 and IL-1β maturation. Moreover, PPARγ interfered with NLRP3 inflammasome formation by decreasing NLRP3-ASC and NLRP3-NLRP3 interactions as well as NLRP3-dependent ASC oligomerization, which is mediated through interaction between the PPARγ DNA-binding domain and the nucleotide-binding and leucine-rich repeat domains of NLRP3. Furthermore, PPARγ was required to limit metabolic damage-associated molecular pattern-induced NLRP3 inflammasome activation in mouse macrophages. Finally, the mature caspase-1/PPARγ ratio was reduced in circulating mononuclear cells of obese patients after weight-loss surgery, which we define as an "NLRP3 accelerating index". Conclusions: These results revealed an additional anti-inflammatory role for PPARγ in suppressing NLRP3 inflammasome activation through interaction with NLRP3. Thus, our study highlights that PPARγ agonism may be a therapeutic option for targeting NLRP3-related metabolic diseases.
| S-EPMC7797672 | biostudies-literature
Project description:ObjectiveTo evaluate whether colchicine treatment was associated with the inhibition of NLRP3 inflammasome activation in patients with COVID-19.MethodsWe present a post hoc analysis from a double-blinded placebo-controlled randomized clinical trial (RCT) on the effect of colchicine for the treatment of COVID-19. Serum levels of NOD-like receptor protein 3 (NLRP3) inflammasome products-active caspase-1 (Casp1p20), IL-1β, and IL-18-were assessed at enrollment and after 48-72 h of treatment in patients receiving standard-of-care (SOC) plus placebo vs. those receiving SOC plus colchicine. The colchicine regimen was 0.5 mg tid for 5 days, followed by 0.5 mg bid for another 5 days.ResultsThirty-six patients received SOC plus colchicine, and thirty-six received SOC plus placebo. Colchicine reduced the need for supplemental oxygen and the length of hospitalization. On Days 2-3, colchicine lowered the serum levels of Casp1p20 and IL-18, but not IL-1β.ConclusionTreatment with colchicine inhibited the activation of the NLRP3 inflammasome, an event triggering the 'cytokine storm' in COVID-19.Trial registration numbersRBR-8jyhxh.
| S-EPMC10013297 | biostudies-literature
Project description:Macrophage migration inhibitory factor (MIF) exerts multiple effects on immune cells, as well as having functions outside the immune system. MIF can promote inflammation through the induction of other cytokines, including TNF, IL-6, and IL-1 family cytokines. Here, we show that inhibition of MIF regulates the release of IL-1α, IL-1β, and IL-18, not by affecting transcription or translation of these cytokines, but via activation of the NLRP3 inflammasome. MIF is required for the interaction between NLRP3 and the intermediate filament protein vimentin, which is critical for NLRP3 activation. Further, we demonstrate that MIF interacts with NLRP3, indicating a role for MIF in inflammasome activation independent of its role as a cytokine. These data advance our understanding of how MIF regulates inflammation and identify it as a factor critical for NLRP3 inflammasome activation.
| S-EPMC5993818 | biostudies-literature
Project description:Mycobacterium kansasii has emerged as an important nontuberculous mycobacterium pathogen, whose incidence and prevalence have been increasing in the last decade. M. kansasii can cause pulmonary tuberculosis clinically and radiographically indistinguishable from that caused by Mycobacterium tuberculosis infection. Unlike the widely-studied M. tuberculosis, little is known about the innate immune response against M. kansasii infection. Although inflammasome activation plays an important role in host defense against bacterial infection, its role against atypical mycobacteria remains poorly understood. In this report, the role of inflammasome activity in THP-1 macrophages against M. kansasii infection was studied. Results indicated that viable, but not heat-killed, M. kansasii induced caspase-1-dependent IL-1? secretion in macrophages. The underlying mechanism was found to be through activation of an inflammasome containing the NLR (Nod-like receptor) family member NLRP3 and the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD). Further, potassium efflux, lysosomal acidification, ROS production and cathepsin B release played a role in M. kansasii-induced inflammasome activation. Finally, the secreted IL-1? derived from caspase-1 activation was shown to restrict intracellular M. kansasii. These findings demonstrate a biological role for the NLRP3 inflammasome in host defense against M. kansasii.
| S-EPMC3340363 | biostudies-literature
Project description:NLRP3 inflammasome is a critical immune component that plays a crucial role in mounting innate immune responses. The deleterious effects of inflammasome activation have been correlated with the COVID-19 disease severity. In the presence of several underlying disorders, the immune components of our bodies are dysregulated, creating conditions that could adversely affect us other than providing a required level of protection. In this review, we focused on the occurrence of NLRP3 inflammasome activation in response to SARS-COV-2 infection, dysregulation of NLRP3 activation events in the presence of several comorbidities, the contribution of activated NLRP3 inflammasome to the severity of COVID-19, and available therapeutics for the treatment of such NLRP3 inflammasome related diseases based on current knowledge. The primed state of immunity in individuals with comorbidities (risk factors) could accelerate many deaths and severe COVID-19 cases via activation of NLRP3 inflammasome and the release of downstream inflammatory molecules. Therefore, a detailed understanding of the host-pathogen interaction is needed to clarify the pathophysiology and select a potential therapeutic approach.
| S-EPMC8613976 | biostudies-literature
Project description:Persistent immune activation is linked to an increased risk of cardiovascular disease (CVD) in people with HIV (PWH) on antiretroviral therapy (ART). The NLRP3 inflammasome may contribute to elevated CVD risk in PWH. This study utilized peripheral blood mononuclear cells (PBMCs) from 25 PWH and 25 HIV-negative controls, as well as HIV in vitro infections. Transcriptional changes were analyzed using RNAseq and pathway analysis. Our results showed that in vitro HIV infection of macrophages and PBMCs from PWH had increased foam cell formation and expression of the NLRP3 inflammasome components and downstream cytokines (caspase-1, IL-1β, and IL-18), which was reduced with inhibition of NLRP3 activity using MCC950. Transcriptomic analysis revealed an increased expression of multiple genes involved in lipid metabolism, cholesterol storage, coronary microcirculation disorders, ischemic events, and monocyte/macrophage differentiation and function with HIV infection and oxLDL treatment. HIV infection and NLRP3 activation increased foam cell formation and expression of proinflammatory cytokines, providing insights into the mechanisms underlying HIV-associated atherogenesis. This study suggests that HIV itself may contribute to increased CVD risk in PWH. Understanding the involvement of the inflammasome pathway in HIV atherosclerosis can help identify potential therapeutic targets to mitigate cardiovascular risks in PWH.
| S-EPMC10889596 | biostudies-literature
Project description:Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne virus that causes hemorrhagic fever. Previous studies showed that SFTSV-infected patients exhibited elevated levels of pro-inflammatory cytokines like interleukin-1β (IL-1β), indicating that SFTSV infection may activate inflammasomes. However, the detailed mechanism remains poorly understood. Herein, we found that SFTSV could stimulate the IL-1β secretion in the infected human peripheral blood mononuclear cells (PBMCs), human macrophages, and C57/BL6 mice. We demonstrate that the maturation and secretion of IL-1β during SFTSV infection is mediated by the nucleotide and oligomerization domain, leucine-rich repeat-containing protein family, pyrin-containing domain 3 (NLRP3) inflammasome. This process is dependent on protease caspase-1, a component of the NLRP3 inflammasome complex. For the first time, our study discovered the role of NLRP3 in response to SFTSV infection. This finding may lead to the development of novel drugs to impede the pathogenesis of SFTSV infection.
| S-EPMC7940371 | biostudies-literature
Project description:Allergic contact dermatitis is a common occupational disease that manifests as a cell-mediated hypersensitivity reaction following skin exposure to small reactive chemicals termed haptens. Haptens penetrate the stratum corneum and covalently modify proteins in the epidermis, inducing intracellular stress, which further leads to the release of damage-associated molecular patterns (DAMPs), such as uric acid, reactive oxygen species, hyaluronic acid fragments and extracellular adenosine triphosphate (ATP). These DAMPs are recognized by pattern recognition receptors (PRRs) in innate immune cells, namely dendritic cells (DCs), leading to their maturation and migration to the draining lymph nodes where they activate naïve T lymphocytes. Among all PRRs, several studies emphasize the role of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome on the allergic contact dermatitis (ACD) sensitization phase. However, skin allergens-danger signals-NLRP3 inflammasome axis is yet to be completely elucidated. Therefore, in this review, we sought to discuss the molecular mechanisms underlying DAMPs release and NLRP3 inflammasome activation triggered by skin allergens. The elucidation of these key events might help to identify novel therapeutic strategies for ACD, as well as the development of nonanimal alternative methods for the identification and potency categorization of skin sensitizers.
| S-EPMC7560080 | biostudies-literature
Project description:BackgroundNeospora caninum is an intracellular parasite that causes significant economic losses in cattle industry. Understanding the host resistance mechanisms in the innate immune response to neosporosis could facilitate the exploration of approaches for controlling N. caninum infection. The NLR inflammasome is a multiprotein platform in the cell cytoplasm and plays critical roles in the host response against microbes.MethodsNeospora caninum-infected wild-type (WT) macrophages and Nlrp3 -/- macrophages, and inhibitory approaches were used to investigate inflammasome activation and its role in N. caninum infection. Inflammasome RT Profiler PCR Arrays were used to identify the primary genes involved in N. caninum infection. The expression of the sensor protein NLRP3, processing of caspase-1, secretion of IL-1β and cell death were detected. Neospora caninum replication in macrophages was also assessed.ResultsMany NLR molecules participated in the recognition of N. caninum, especially the sensor protein NLRP3, and further study revealed that the NLRP3 distribution became punctate in the cell cytoplasm, which facilitated inflammasome activation. Inflammasome activation-mediated caspase-1 processing and IL-1β cleavage in response to N. caninum infection were observed and were correlated with the time of infection and number of infecting parasites. LDH-related cell death was also observed, and this death was regarded as beneficial for the clearance of N. caninum. Treatment of N. caninum-infected macrophages with caspase-1, pan-caspase and NLRP3 inhibitors led to the impaired release of active IL-1β and a failure to restrict parasite replication. And Neospora caninum infected peritoneal macrophages from Nlrp3-deficient mice displayed greatly decreased release of active IL-1β and the failure of caspase-1 cleavage.ConclusionsThe NLRP3 inflammasome can be activated in N. caninum-infected macrophages, and plays a protective role in the host response to control N. caninum.
| S-EPMC5450200 | biostudies-literature