The NLRP3 Inflammasome as a Pharmacological Target

Marchetti, Carlo

doi:10.1097/fjc.0000000000000718

Cited by 23 publications

(13 citation statements)

References 112 publications

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“…Using cancer databases, we found higher expression of NLRP3 in skin biopsies of melanoma lesions compared to normal skin and with NLRP3 expression positively correlated with expression of IL-1β. Notably, in normal tissues NLRP3 is absent or at very low abundance (28). We demonstrate active NLRP3 inflammasome in malignant melanoma skin biopsies.…”

Section: Discussionmentioning

confidence: 64%

Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion

Tengesdal

Menon

Osborne

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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118

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Interleukin-1β (IL-1β)–mediated inflammation suppresses antitumor immunity, leading to the generation of a tumor-permissive environment, tumor growth, and progression. Here, we demonstrate that nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in melanoma is linked to IL-1β production, inflammation, and immunosuppression. Analysis of cancer genome datasets (TCGA and GTEx) revealed greater NLRP3 and IL-1β expression in cutaneous melanoma samples (n = 469) compared to normal skin (n = 324), with a highly significant correlation between NLRP3 and IL-1β (P < 0.0001). We show the formation of the NLRP3 inflammasome in biopsies of metastatic melanoma using fluorescent resonance energy transfer analysis for NLRP3 and apoptosis-associated speck-like protein containing a CARD. In vivo, tumor-associated NLRP3/IL-1 signaling induced expansion of myeloid-derived suppressor cells (MDSCs), leading to reduced natural killer and CD8+ T cell activity concomitant with an increased presence of regulatory T (Treg) cells in the primary tumors. Either genetic or pharmacological inhibition of tumor-derived NLRP3 by dapansutrile (OLT1177) was sufficient to reduce MDSCs expansion and to enhance antitumor immunity, resulting in reduced tumor growth. Additionally, we observed that the combination of NLRP3 inhibition and anti–PD-1 treatment significantly increased the antitumor efficacy of the monotherapy by limiting MDSC-mediated T cell suppression and tumor progression. These data show that NLRP3 activation in melanoma cells is a protumor mechanism, which induces MDSCs expansion and immune evasion. We conclude that inhibition of NLRP3 can augment the efficacy of anti–PD-1 therapy.

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Section: Discussionmentioning

confidence: 64%

Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion

Tengesdal

Menon

Osborne

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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118

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“…Therefore, we tested the NLRP3 inhibitor dapansutrile (OLT1177) in APP/PS1 mice using two different oral doses of the inhibitor administered in the animals' feed. OLT1177 was shown to have beneficial effects in a murine model for acute arthritis by suppressing joint inflammation and in addition reduces the infarct size after ischemia reperfusion injury in the mouse (45)(46)(47). The pharmacokinetics and safety of OLT1177 has been characterized after oral administration to healthy volunteers in a phase 1 trial (17).…”

Section: Discussionmentioning

confidence: 99%

The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer’s disease

Lonnemann

Hosseini

Marchetti

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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179

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Numerous studies demonstrate that neuroinflammation is a key player in the progression of Alzheimer’s disease (AD). Interleukin (IL)-1β is a main inducer of inflammation and therefore a prime target for therapeutic options. The inactive IL-1β precursor requires processing by the the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome into a mature and active form. Studies have shown that IL-1β is up-regulated in brains of patients with AD, and that genetic inactivation of the NLRP3 inflammasome improves behavioral tests and synaptic plasticity phenotypes in a murine model of the disease. In the present study, we analyzed the effect of pharmacological inhibition of the NLRP3 inflammasome using dapansutrile (OLT1177), an oral NLRP3-specific inhibitor that is safe in humans. Six-month-old WT and APP/PS1 mice were fed with standard mouse chow or OLT1177-enriched chow for 3 mo. The Morris water maze test revealed an impaired learning and memory ability of 9-mo-old APP/PS1 mice (P = 0.001), which was completely rescued by OLT1177 fed to mice (P = 0.008 to untreated APP/PS1). Furthermore, our findings revealed that 3 mo of OLT1177 diet can rescue synaptic plasticity in this mouse model of AD (P = 0.007 to untreated APP/PS1). In addition, microglia were less activated (P = 0.07) and the number of plaques was reduced in the cortex (P = 0.03) following NLRP3 inhibition with OLT1177 administration. We also observed an OLT1177 dose-dependent normalization of plasma metabolic markers of AD to those of WT mice. This study suggests the therapeutic potential of treating neuroinflammation with an oral inhibitor of the NLRP3 inflammasome.

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“…The intracellular processing of IL-1β into its biologically active form is largely governed by cytosolic macromolecular complexes termed inflammasomes (Franchi et al 2009, Marchetti 2019). Notably, it has been observed that viral proteins of the SARS-CoV virus ORF3a, ORF8b and Viroporin 3a activate the NLRP3 inflammasome (Chen et al 2019, Shi et al 2019, Siu et al 2019).…”

Section: Introductionmentioning

confidence: 99%

Targeting of the NLRP3 Inflammasome for early COVID-19

Marchetti

Mould

Tengesdal

et al. 2021

Preprint

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Following entry and replication of Severe Acute Respiratory Syndrome-coronavirus 2 (SARS-CoV-2) into ACE2 expressing cells, the infected cells undergo lysis releasing more virus but also cell contents. In the lung, constitutive cytokines such as IL-1α are released together with other cell contents. A cascade of inflammatory cytokines ensues, including chemokines and IL-1β, triggering both local as well as systemic inflammation. This cascade of inflammatory cytokines in patients with COVID-19 is termed Cytokine Release Syndrome (CRS), and is associated with poor outcomes and death. Many studies reveal that blocking IL-1β activities in COVID-19 patients reduces disease severity and deaths. Here we report highly significant circulating levels of IL-1β, IL-1 Receptor antagonist, IL-6, TNFα, IL-10 and soluble urokinase plasminogen activator receptor in COVID-19 patients with mild or no symptoms. We also report that in circulating myeloid cells from the same patients, there is increased expression of the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) early in the infection. We observed increased NLRP3 gene expression in myeloid cells correlated with IL-1β gene expression and also with elevated circulating IL-1β levels. We conclude that early in SARS-CoV-2 infection, NLRP3 activation takes place and initiates the CRS. Thus, NLRP3 is a target to reduce the organ damage of inflammatory cytokines of the CRS.

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The NLRP3 Inflammasome as a Pharmacological Target

Cited by 23 publications

References 112 publications

Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion

Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion

The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer’s disease

Targeting of the NLRP3 Inflammasome for early COVID-19

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