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      POP1 inhibits MSU-induced inflammasome activation and ameliorates gout

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          Abstract

          Canonical inflammasomes are innate immune protein scaffolds that enable the activation of inflammatory caspase-1, and subsequently the processing and release of interleukin (IL)-1β, IL-18, and danger signals, as well as the induction of pyroptotic cell death. Inflammasome assembly and activation occurs in response to sensing of infectious, sterile and self-derived molecular patterns by cytosolic pattern recognition receptors, including the Nod-like receptor NLRP3. While these responses are essential for host defense, excessive and uncontrolled NLRP3 inflammasome responses cause and contribute to a wide spectrum of inflammatory diseases, including gout. A key step in NLRP3 inflammasome assembly is the sequentially nucleated polymerization of Pyrin domain (PYD)- and caspase recruitment domain (CARD)-containing inflammasome components. NLRP3 triggers polymerization of the adaptor protein ASC through PYD-PYD interactions, but ASC polymerization then proceeds in a self-perpetuating manner and represents a point of no return, which culminates in the activation of caspase-1 by induced proximity. In humans, small PYD-only proteins (POPs) lacking an effector domain regulate this key process through competitive binding, but limited information exists on their physiological role during health and disease. Here we demonstrate that POP1 expression in macrophages is sufficient to dampen MSU crystal-mediated inflammatory responses in animal models of gout. Whether MSU crystals are administered into a subcutaneous airpouch or into the ankle joint, the presence of POP1 significantly reduces neutrophil infiltration. Also, airpouch exudates have much reduced IL-1β and ASC, which are typical pro-inflammatory indicators that can also be detected in synovial fluids of gout patients. Exogenous expression of POP1 in mouse and human macrophages also blocks MSU crystal-induced NLRP3 inflammasome assembly, resulting in reduced IL-1β and IL-18 secretion. Conversely, reduced POP1 expression in human macrophages enhances IL-1β secretion. We further determined that the mechanism for the POP1-mediated inhibition of NLRP3 inflammasome activation is through its interference with the crucial NLRP3 and ASC interaction within the inflammasome complex. Strikingly, administration of an engineered cell permeable version of POP1 was able to ameliorate MSU crystal-mediated inflammation in vivo, as measured by neutrophil infiltration. Overall, we demonstrate that POP1 may play a crucial role in regulating inflammatory responses in gout.

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          Most cited references56

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          The NLRP3 inflammasome: molecular activation and regulation to therapeutics

          NLRP3 (NACHT, LRR and PYD domains-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase-1-dependent release of the proinflammatory cytokines, IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical basis of NLRP3 activation and regulation, and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome.
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            A role for mitochondria in NLRP3 inflammasome activation.

            An inflammatory response initiated by the NLRP3 inflammasome is triggered by a variety of situations of host 'danger', including infection and metabolic dysregulation. Previous studies suggested that NLRP3 inflammasome activity is negatively regulated by autophagy and positively regulated by reactive oxygen species (ROS) derived from an uncharacterized organelle. Here we show that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome. Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. Notably, both ROS generation and inflammasome activation are suppressed when mitochondrial activity is dysregulated by inhibition of the voltage-dependent anion channel. This indicates that NLRP3 inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases.
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              Gout-associated uric acid crystals activate the NALP3 inflammasome.

              Development of the acute and chronic inflammatory responses known as gout and pseudogout are associated with the deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints and periarticular tissues. Although MSU crystals were first identified as the aetiological agent of gout in the eighteenth century and more recently as a 'danger signal' released from dying cells, little is known about the molecular mechanisms underlying MSU- or CPPD-induced inflammation. Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1beta and IL-18. Macrophages from mice deficient in various components of the inflammasome such as caspase-1, ASC and NALP3 are defective in crystal-induced IL-1beta activation. Moreover, an impaired neutrophil influx is found in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL-1beta receptor (IL-1R). These findings provide insight into the molecular processes underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                26 September 2022
                2022
                : 13
                : 912069
                Affiliations
                [1] 1 Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, IL, United States
                [2] 2 Department of Academic Pathology, Cedars Sinai Medical Center , Los Angeles, CA, United States
                [3] 3 Department of Biomedical Sciences, Cedars Sinai Medical Center , Los Angeles, CA, United States
                [4] 4 The Kao Autoimmunity Institute, Cedars Sinai Medical Center , Los Angeles, CA, United States
                [5] 5 Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center , Los Angeles, CA, United States
                Author notes

                Edited by: Amiram Ariel, University of Haifa, Israel

                Reviewed by: Jonathan A. Harton, Albany Medical College, United States; Guangbi Li, Virginia Commonwealth University, United States; Eun-Kyeong Jo, Chungnam National University, South Korea

                *Correspondence: Andrea Dorfleutner, andrea.dorfleutner@ 123456cshs.org ; Christian Stehlik, christian.stehlik@ 123456csmc.edu

                This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2022.912069
                9550078
                36225929
                b12614c6-c192-4f2f-bd1b-1f70de447e00
                Copyright © 2022 de Almeida, Devi, Indramohan, Huang, Ratsimandresy, Pope, Dorfleutner and Stehlik

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 03 April 2022
                : 06 September 2022
                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 56, Pages: 13, Words: 6770
                Funding
                Funded by: National Institutes of Health , doi 10.13039/100000002;
                Award ID: AI099009 , AR064349 , AI134030, AI140702 , AI120625 , AI165797
                Funded by: Pfizer , doi 10.13039/100004319;
                Award ID: WI223665
                Funded by: American Heart Association , doi 10.13039/100000968;
                Award ID: 18CDA34110296
                Categories
                Immunology
                Original Research

                Immunology
                inflammasome,gout,caspase-1,inflammation,macrophage,pyrin domain
                Immunology
                inflammasome, gout, caspase-1, inflammation, macrophage, pyrin domain

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