Molecular Pathophysiology of Gout

The early phase of acute gouty arthritis is characterized by an auto-amplification loop of regulated necrosis and inflammation; MSU crystals trigger both cell necrosis and inflammation in a direct as well as indirect manner. The later phase of gouty arthritis is characterized by the resolution of symptoms despite persistence of MSU crystals. Numerous immunoregulatory pathways as well as aggregated neutrophil extracellular traps contribute to this process. Chronic gout is characterized by tophus formation; that is, masses of MSU crystals and NETs encapsulated by a foreign body reaction involving giant cells, macrophages, and fibroblasts that contribute to the destruction of surrounding tissues. Dissecting the molecular and cellular pathogenesis of gout can help to identify innovative drug targets. Three contradictory clinical presentations of gout have puzzled clinicians and basic scientists for some time: first, the crescendo of sterile inflammation in acute gouty arthritis; second, its spontaneous resolution, despite monosodium urate (MSU) crystal persistence in the synovium; and third, immune anergy to MSU crystal masses observed in tophaceous or visceral gout. Here, we provide an update on the molecular pathophysiology of these gout manifestations, namely, how MSU crystals can trigger the auto-amplification loop of necroinflammation underlying the crescendo of acute gouty arthritis. We also discuss new findings, such as how aggregating neutrophil extracellular traps (NETs) might drive the resolution of arthritis and how these structures, together with granuloma formation, might support immune anergy, but yet promote tissue damage and remodeling during tophaceous gout. Three contradictory clinical presentations of gout have puzzled clinicians and basic scientists for some time: first, the crescendo of sterile inflammation in acute gouty arthritis; second, its spontaneous resolution, despite monosodium urate (MSU) crystal persistence in the synovium; and third, immune anergy to MSU crystal masses observed in tophaceous or visceral gout. Here, we provide an update on the molecular pathophysiology of these gout manifestations, namely, how MSU crystals can trigger the auto-amplification loop of necroinflammation underlying the crescendo of acute gouty arthritis. We also discuss new findings, such as how aggregating neutrophil extracellular traps (NETs) might drive the resolution of arthritis and how these structures, together with granuloma formation, might support immune anergy, but yet promote tissue damage and remodeling during tophaceous gout. aggregated masses of MSU crystals and NETs that can trap and degrade proinflammatory cytokines and chemokines, thereby contributing to the resolution of inflammation. several small proteins that enhance the phagocytic function and induce inflammatory responses in innate immunity. a crystal is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a specific microscopic structure. MSU crystals are an example of crystals formed inside the body during gout. an oxidized dimer of the amino acid cysteine that is slightly soluble in water. proteins released by necrotic cells (i.e., HMGB1 or histones) that can act as danger signals to promote inflammatory responses when released in the extracellular space. small vesicles (0.1–1 μm in diameter) that are released from the plasma membrane into the extracellular space. They comprise proteins, mRNA, and miRNA of the cell of origin. Components and nature of ectosomes vary for different stimuli, and for different states of the cell (resting versus activated). form of arthritis associated with acute onset of joint pain and swelling due to the deposition of MSU crystals. a focal collection of inflammatory cells, such as activated mono- and multinucleated macrophages, neutrophils, cell debris, and lymphocytes, at the site of tissue injury or infection. a co-factor protein that can bind to DNA and regulate gene transcription. It is a well-known DAMP that can induce an inflammatory response when released into the extracellular space. defined as the incompetence of an immune cell to respond against its targets (i.e., foreign substrates, such as pathogens or crystals). members of the kinin-kallikrein system mediating inflammation. conventional designation of a subset of macrophages associated with the production of high amounts of proinflammatory cytokines, such as IL1-β, TNF, IL-12, and so on. They are usually associated with host–pathogen responses and the promotion of TH1 responses. Phenotypically, M1 macrophages express major histocompatibility complex class II (MHC II), the CD68 marker, and co-stimulatory molecules CD80 and CD86. conventional designation of a subset of resident macrophages associated with the production of high amounts of anti-inflammatory cytokines, such as IL-10 and TGF-β, and low levels of proinflammatory cytokine IL-12. Tumor-associated macrophages usually display this phenotype. large white blood cells that can recognize, engulf, and digest cellular debris, microbes, or foreign substances as a consequence of injury or infection. a process whereby cell necrosis and inflammation enhance each other in an auto-amplification loop, such as in the early crescendo phase of gouty arthritis. form of regulated necrosis induced by ligands binding to TNF death domain receptors and followed by phosphorylation of receptor interaction protein kinase 1 (RIPK1) and RIPK3 to form a necrosome complex. The necrosome further activates mixed-lineage kinase-like (MLKL), executing cell death by migrating to the plasma membrane, where it is associated with pore formation and plasma membrane rupture. formed by receptor-interacting protein (RIP) kinase-3 and the pseudokinase mixed-lineage kinase domain-like (MLKL) executing regulated necrosis downstream of RIP kinase-1. upon activation by different stimuli (i.e., bacteria, crystals, LPS, pr PMA), neutrophils can explode and release their chromatin, bearing granular serine proteases to form net-like structures known as NETs. danger signaling platform in the cytosol, comprising mainly macrophages and dendritic cells. It integrates several danger signals into the secretion of IL-1β and IL-18 via activating caspase-1. proteins expressed by innate immune cells that can recognize various pathogens as well as DAMPs. Based on their function and ligand specificity, PRRs can be divided into signaling PRRs (e.g., Toll-like receptors, NOD-like receptors) and endocytic PRRs (i.e., glucan receptors). process of engulfing certain particles, debris, or microorganisms by specialized immune cells, such as neutrophils or macrophages. membrane protein that is part of the TNF cytokine superfamily. It has a key role in the regulation of osteoclast formation. class of a ‘programmed’ form of necrosis that includes multiple cell death pathways with distinct biochemical signaling cascade, such as necroptosis, parthanatos, ferroptosis, pyroptosis, and mitochondrial permeability transition pore (MPTP)-mediated necrosis. a coordinated and active process to restore homeostasis. a condition of joint inflammation caused by bacterial or fungal infection. class of membrane-bound PRRs present on innate immune cells, such as macrophages and dendritic cells, that can recognize pathogens as well as DAMPs and further activate NF-κB signaling and the MAP kinase pathway to generate an inflammatory response. masses of monosodium urate crystals, NETs, and proteins surrounded by foreign-body granuloma-like encapsulating immune cells and fibroblasts. visceral gout is a disease occurring in birds and humans due to impaired kidney function followed by accumulation of urate crystals in different organs. Chronic gout is a more severe condition that occurs in humans after repeated attacks of acute gout. The urate crystals accumulated in both of these conditions lead to the formation of white ‘tophi’ in joints or skin.