Engagement of CD14 Mediates the Inflammatory Potential of Monosodium Urate Crystals

Scott, Peter C.; Ma, Hong; Viriyakosol, Suganya; Terkeltaub, Robert; Liu‐Bryan, Ru

doi:10.4049/jimmunol.177.9.6370

Cited by 140 publications

(117 citation statements)

References 54 publications

(70 reference statements)

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“…MSU is detected at the cell surface by CD14, a phagocyte-expressed pattern recognition receptor that functionally interacts with both TLR2 and TLR4. 31 PGN is also a ligand of TLR2, suggesting that TLR2 or TLR4 might change intracellular K þ levels. Interestingly, TLRs and IL-1R were recently shown to associate and functionally depend on the large-conductance Ca 2 þ -activated K þ channel MaxiK 32,33 Since this K þ channel is abundantly expressed in macrophages, we could speculate that the activators MSU, PGN and probably imidazoquinoline activate the inflammasome via a MaxiK-mediated K þ efflux.…”

Section: Discussionmentioning

confidence: 99%

Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration

et al. 2007

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Section: Discussionmentioning

confidence: 99%

Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration

et al. 2007

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“…CD14 deficiency has been associated with depleted pools of proIL-1␤, decreased caspase 1 activation, and impaired MSU crystal recognition (7). In this study, CD14 expression by early infiltrating monocyte/macrophages was low compared with that by resident macrophages ( Figure 5B).…”

Section: M1 Macrophage Differentiation In Msu-induced Inflammationmentioning

confidence: 78%

“…The generation of proIL-1␤ pools has been shown to be impaired in CD14-knockout macrophages (7). It is therefore possible that the low CD14 expression observed on MSU crystal-recruited monocytes plays a key role in blocking proIL-1␤ accumulation, resulting in a noninflammatory monocyte phenotype.…”

Section: Discussionmentioning

confidence: 99%

Monosodium urate monohydrate crystal–recruited noninflammatory monocytes differentiate into M1‐like proinflammatory macrophages in a peritoneal murine model of gout

Martin

Shaw

Liu

et al. 2011

Arthritis & Rheumatism

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Objective. To profile monosodium urate monohydrate (MSU) crystal-recruited monocyte inflammatory function during the course of in vivo differentiation, in a murine model of peritoneal MSU crystal-induced inflammation.Methods. C57BL/6J mice were injected intraperitoneally with MSU crystals, and the peritoneal cells were harvested at different time points. The MSU crystal-recruited monocyte/macrophage population was analyzed for the expression of differentiation and activation markers, cytokine production following MSU crystal restimulation ex vivo and in vivo, expression of NLRP3-associated proteins (ASC, caspase 1) and prointerleukin-1␤ (proIL-1␤), and phagocytic capacity.Results. Monocytes recruited 8 hours after MSU crystal stimulation (F4/80 low Gr-1 int 7/4؉) exhibited poor phagocytic capacity, expressed low levels of proIL-1␤, and failed to produce proinflammatory cytokines in response to MSU crystal restimulation. In the absence of MSU crystal restimulation, differentiating monocytes produced low levels of transforming growth factor ␤1 ex vivo, and this was abrogated following MSU crystal restimulation. Over time these cells developed a proinflammatory phenotype in vivo, characterized by the production of IL-1␤, tumor necrosis factor ␣, IL-6, CCL2 (monocyte chemotactic protein 1), and CXCL1 (cytokine-induced neutrophil chemoattractant) following ex vivo MSU crystal restimulation, and leading to IL-1␤ production and cell infiltration following MSU crystal rechallenge in vivo. Proinflammatory function was associated with differentiation toward a macrophage phenotype (F4/80 high Gr-1-7/4-), an increase in phagocytic capacity, and an increase in the expression of proIL-1␤. Conclusion. MSU crystal-recruited monocytes differentiate into proinflammatory M1-like macrophages in vivo. This proinflammatory macrophage phenotype is likely to play a key role in perpetuating inflammation in gouty arthritis in the presence of ongoing deposition of fresh MSU crystals.Acute gout is an intensely painful form of inflammatory arthritis caused by the formation of monosodium urate monohydrate (MSU) crystals in the joint and connective tissues. An acute attack of gout is characterized by intense pain and swelling and reddening of the skin around the affected area. Without treatment this inflammatory response will resolve naturally over 7-10 days.Interleukin-1␤ (IL-1␤) has been identified as a pivotal cytokine in gout and MSU crystal-induced inflammation (1-3). More recently, studies have identified IL-1␤ production following activation of the NLRP3 inflammasome in resident macrophages as a key event in the initiation of an attack of acute gout (4-7). However, there is a growing body of evidence indicating that cells of the monocyte/macrophage lineage play a pivotal role not only in the initiation but also in the progression and resolution of acute gouty inflammation.It has been proposed that the self-limiting nature of an acute gout attack is linked to the differentiation state of the MSU crystal-recruited monocyte population. In...

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“…Uric acid released by dying cells interacts with extracellular sodium to form MSU, which acts as a danger signal. The phagocytosis of cell debris combined with the MSU signal induce maturation and activation of dendritic cells [66], possibly also caused by MSU interactions with CD14, an adaptor molecule for TLR2 and TLR4 [67]. MSU and calcium pyrophosphate dehydrate (CPPD) crystals can induce activation of the NLRP3 inflammasome resulting in production of IL-1 [68][69][70].…”

Section: Protein Misfolding and Proteotoxic Stress In Non-mendelian Imentioning

confidence: 99%

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

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Cells have a number of mechanisms to maintain protein homeostasis, including proteasomemediated degradation of ubiquitinated proteins and autophagy, a regulated process of 'self-eating' where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by tolllike receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses.Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.3 Cells must maintain a delicate balance between the demands for protein synthesis and the need to avoid accumulation of incompletely processed or unfolded proteins that can accumulate under normal conditions and even more so when cells face a variety of stresses. The unfolded protein response (UPR) is an evolutionarily conserved mechanism to maintain cellular homeostasis by preventing the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Disturbed protein folding in the ER is primarily detected by three transmembrane (TM) proteins: activating transcription factor 6 (ATF6), inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). The combined action of these sensors reduces global protein synthesis while upregulating the production of chaperone proteins that can stabilize misfolded proteins. Apart from ER homeostasis, the UPR can modulate other biological functions, including apoptosis, protein secretion, and as we will discuss further, inflammatory responses [1,2].A series of molecular changes are initiated in response to cellular stressors in order to minimize damage caused by unfavorable environmental conditions, such as temperature changes, toxins (e.g. bacterial, chemical), radiation, mechanical damage, nutritional status as well as incompletely folded proteins intracellularly (Figure 1). The UPR serves the adaptive purpose of protecting the cell by activating a series of mechanisms including the induction of molecular chaperones to assist with correct folding -e.g. heat shock proteins and foldases. Interestingly there are a number of connections between the UPR and inflammatory signaling pat...

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Engagement of CD14 Mediates the Inflammatory Potential of Monosodium Urate Crystals

Cited by 140 publications

References 54 publications

Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration

Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration

Monosodium urate monohydrate crystal–recruited noninflammatory monocytes differentiate into M1‐like proinflammatory macrophages in a peritoneal murine model of gout

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

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