Monosodium Urate Crystals Synergize with IFN-γ to Generate Macrophage Nitric Oxide: Involvement of Extracellular Signal-Regulated Kinase 1/2 and NF-κB

Jaramillo, Maritza; Naccache, Paul H.; Olivier, Martin

doi:10.4049/jimmunol.172.9.5734

Cited by 66 publications

(56 citation statements)

References 60 publications

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“…Indeed, the role of these factors in the transcriptional control of chemokine genes has been extensively documented (26,33,39,44) and has been linked to ERK1/2 activation (26,32). These results are perfectly in line with our published data showing that the up-regulating effect of MSU crystals on interferon-␥-mediated nitric oxide production occurred via ERK1/2-dependent NF-B activation (29). Thus, it is likely that through the activation of the same second messengers, MSU crystals modulate different macrophage functions, including multiple chemokine expression and amplification of macrophage responses to interferon-␥ (e.g.…”

Section: Discussionsupporting

confidence: 83%

“…Thus, based on these previous works, along with our data, it is plausible that MSU crystal-inducible macrophage MIP-2 contributes to neutrophil infiltration during acute gout. Although neutrophils account for most of the leukocytes recruited in response to MSU crystals (ϳ90%), a much smaller but still significant monocyte population (ϳ10%) is also observed (8,12,29). The mechanisms explaining monocyte migration into synovial tissue are not clearly defined; however, accumulating evidence indicates that one potential candidate is MCP-1 (8,12), a strong monocyte chemoattractant and activator (4).…”

Section: Discussionmentioning

confidence: 99%

“…The absence of contamination by endotoxins in the MSU preparations was confirmed by performing the Limulus amebocyte lysate test (Etoxate kit (Sigma)) as well as nitric oxide measurements in presence of Polymixin B (Sigma) (data not shown), as we previously described (29). Isotopes [␣-32 P]dCTP (3000 Ci/mmol) and [␥-32 P]dATP (3000 Ci/mmol) were purchased from ICN Pharmaceuticals Canada Ltd. (Montréal, Québec, Canada).…”

Section: Methodsmentioning

confidence: 99%

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Signaling Events Involved in Macrophage Chemokine Expression in Response to Monosodium Urate Crystals

Jaramillo

Godbout

Naccache

et al. 2004

Journal of Biological Chemistry

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Chemokine production has been associated with leukocyte infiltration into the joint during gouty arthritis, and monosodium urate (MSU) crystals, the causative agent of this arthropathy, have been shown to modulate their expression. In the present study, we investigated the transductional mechanisms underlying this cellular regulation in the murine macrophage cell line B10R. We report that MSU crystals rapidly and transiently increase mRNA levels of various chemokines in a concentration-dependent manner. Examination of second messenger activation revealed that macrophage exposure to MSU crystals led to MEK1/2, ERK1/2, and inhibitory protein B␣ phosphorylation as well as to NF-B and AP-1 nuclear translocation. Of interest, specific blockage of the ERK1/2 pathway drastically reduced up-modulation of MSU crystal-mediated chemokine production and activation of nuclear factors. Similarly, selective inhibition of NF-B suppressed NF-B DNA binding activity and the induction of all chemokine transcripts. These findings indicate that ERK1/2-dependent signals seem to be required for AP-1 and NF-B activation and subsequent mRNA expression of the various macrophage chemokines. In addition, transcription and stability assays performed in presence of actinomycin D showed that MSU crystal-mediated MIP-1␤ mRNA up-regulation resulted solely from transcriptional control, whereas that of MIP-1␣, MIP-2, and MCP-1 was due to both gene transcription activation and mRNA posttranscriptional stabilization. Overall, the results of this study help to define the molecular events that govern macrophage chemokine regulation in response to MSU crystals, which is of paramount importance to better understand, and eventually to tame, the inflammatory response during acute gout.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Signaling Events Involved in Macrophage Chemokine Expression in Response to Monosodium Urate Crystals

Jaramillo

Godbout

Naccache

et al. 2004

Journal of Biological Chemistry

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“…Several mechanisms have been proposed to explain an association between SUA and essential hypertension, including impairment of vascular nitric oxide activity, 29 decreased production of nitric oxide 30 and activation of the renin-angiotensin system (RAS), 31,32 stimulation of vascular smooth muscle cell proliferation. 33,34 In addition, elevated SUA concentration is also associated with insulin resistance, 35 high triglyceride levels, 36 proinflammatory, chronic inflammation 37,38 and increased arterial stiffness, 39 all of which may affect the development of hypertension.…”

Section: Uric Acid and Elderly Hypertension Z Lu Et Almentioning

confidence: 99%

Serum uric acid level in primary hypertension among Chinese nonagenarians/centenarians

Dong

He-ping

et al. 2008

J Hum Hypertens

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Epidemiologic studies suggest an independent positive association of elevated serum uric acid with essential hypertension. However, to date, limited information is available in the old population. In the present study, we included 832 unrelated Chinese nonagenarians/centenarians (269 men and 563 women; ranged in age from 90 to 108 years (mean, 94.6±4.0)). The mean serum uric acid level was 320 lmol l À1 (standard deviation 87 lmol l À1). After adjustment for age, body mass index, waist-to-hip ratio, smoking habits, tea habits, alcohol consumption, fasting plasma glucose, plasma lipids and serum creatinine, the odds ratio comparing the highest with lowest quartile of serum uric acid were 0.67 (95% confidence interval (CI), 0.33-1.21) and 1.36 (95% CI, 0.88-2.22) in men and women, respectively. When compared with normotensive subjects, we did not observe statistical higher serum uric acid levels in subjects with hypertension. In summary, we found that serum uric acid level is not directly correlated with hypertension among Chinese nonagenarians/centenarians.

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“…These data would indicate that monocytes drive and differentiated macrophages resolve inflammation in gout. However, other studies show that MSU crystals induce a classic proinflammatory response in both primary and bone marrow-derived macrophages (3,4,(11)(12)(13)(14), indicating a key role for macrophages in the initiation of the inflammatory cascade. In addition, there is evidence to suggest that upon recruitment to the site of inflammation, early infiltrating monocytes do not exhibit a proinflammatory phenotype and therefore may not be driving the early phase of inflammation in gout (5).…”

mentioning

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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Monosodium Urate Crystals Synergize with IFN-γ to Generate Macrophage Nitric Oxide: Involvement of Extracellular Signal-Regulated Kinase 1/2 and NF-κB

Cited by 66 publications

References 60 publications

Signaling Events Involved in Macrophage Chemokine Expression in Response to Monosodium Urate Crystals

Signaling Events Involved in Macrophage Chemokine Expression in Response to Monosodium Urate Crystals

Serum uric acid level in primary hypertension among Chinese nonagenarians/centenarians

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

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