Uric Acid Is a Danger Signal Activating NALP3 Inflammasome in Lung Injury Inflammation and Fibrosis

Gasse, Paméla; Riteau, Nicolas; Charron, Sabine; Girre, Sandra; Fick, Lizette; Pétrilli, Virginie; Tschopp, Jürg; Lagente, Vincent; Quesniaux, Valérie; Ryffel, Bernhard; Couillin, Isabelle

doi:10.1164/rccm.200808-1274oc

Cited by 373 publications

(287 citation statements)

References 54 publications

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“…Taken together, these findings suggest that the loss of inflammasome components hinders the progression of the FBR possibly through the attenuation of profibrotic signals. Consistent with this suggestion, the inability to form the inflammasome has been shown to be associated with reduced fibrosis in injury models of liver fibrosis, myocardial ischemia/reperfusion, unilateral ureteral obstruction, and bleomycin (BLM)-induced lung injury (24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 71%

Inflammasome components Asc and caspase-1 mediate biomaterial-induced inflammation and foreign body response

Malik

Hoque

Ouyang

et al. 2011

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

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Implantation of biomaterials and devices into soft tissues leads to the development of the foreign body response (FBR), which can interfere with implant function and eventually lead to failure. The FBR consists of overlapping acute and persistent inflammatory phases coupled with collagenous encapsulation and currently there are no therapeutic options. Initiation of the FBR involves macrophage activation, proceeding to giant cell formation, fibroblast activation, and collagen matrix deposition. Despite the recognition of this sequence of events, the molecular pathways required for the FBR have not been elucidated. We have identified that the acute inflammatory response to biomaterials requires nucleotide-binding domain and leucine-rich repeat-containing 3 (Nlrp3), apoptosis-associated speck-like protein containing CARD (Asc), and caspase-1, as well as plasma membrane cholesterol, and Syk signaling. Full development of the FBR is dependent on Asc and caspase-1, but not Nlrp3. The common antiinflammatory drug aspirin can reduce inflammasome activation and significantly reduce the FBR. Taken together, these findings expand the role of the inflammasome from one of sensing damage associated molecular patterns (DAMPs) to sensing all particulate matter irrespective of size. In addition, implication of the inflammasome in biomaterial recognition identifies key pathways, which can be targeted to limit the FBR.

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Section: Discussionmentioning

confidence: 71%

Inflammasome components Asc and caspase-1 mediate biomaterial-induced inflammation and foreign body response

Malik

Hoque

Ouyang

et al. 2011

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

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“…Increasing numbers of DAMPs are being reported as candidate agonists of TLRs, and particularly TLR4, including heat shock proteins (HSPs) (HSP70, HSP90), [16][17][18] high-mobility group box 1 (HMGB1) 19,20 and uric acid crystals. 21 These molecules can bind to TLR4, thereby causing inflammatory responses and providing DCs with danger signals, which can be translated into the promotion of an anti-tumor T-cell response. Supporting these findings, patients with breast cancer who have lost TLR4 function have been shown to relapse more quickly after chemotherapy than patients with normal TLR4 expression.…”

Section: Introductionmentioning

confidence: 99%

TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells

et al. 2013

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The combination of immunotherapy and chemotherapy is regarded as a promising approach for the treatment of certain types of cancer. However, the underlying mechanisms need to be fully investigated to guide the design of more efficient protocols for cancer chemoimmunotherapy. It is well known that danger-associated molecular patterns (DAMPs) can activate immune cells, including dendritic cells (DCs), via Toll-like receptors (TLRs); however, the role of DAMPs released from chemical drug-treated tumor cells in the activation of the immune response needs to be further elucidated. Here, we found that colorectal cancer (CRC) cells treated with oxaliplatin (OXA) and/or 5-fluorouracil (5-Fu) released high levels of high-mobility group box 1 (HMGB1) and heat shock protein 70 (HSP70). After OXA/5-Fu therapy, the sera of CRC patients also exhibited increased levels of HMGB1 and HSP70, both of which are well-known DAMPs. The supernatants of dying CRC cells treated with OXA/5-Fu promoted mouse and human DC maturation, with upregulation of HLA-DR, CD80 and CD86 expression and enhancement of IL-1b, TNF-a, MIP-1a, MIP-1b, RANTES and IP-10 production. Vaccines composed of DCs pulsed with the supernatants of chemically stressed CRC cells induced a more significant IFN-c-producing Th1 response both in vitro and in vivo. However, the supernatants of chemically stressed CRC cells failed to induce phenotypic maturation and cytokine production in TLR4-deficient DCs, indicating an essential role of TLR4 in DAMP-induced DC maturation and activation. Furthermore, pulsing with the supernatants of chemically stressed CRC cells did not efficiently induce an IFN-c-producing Th1 response in TLR4-deficient DCs. Collectively, these results demonstrate that DAMPs released from chemically stressed cancer cells can activate DCs via TLR4 and enhance the induction of an anti-tumor T-cell immune response, delineating a clinically relevant immuno-adjuvant pathway triggered by DAMPs.

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“…Uric acid is not only a byproduct of cell death, but recent research has discovered that it is a mediator of inflammation and tissue damage 2 . Uric acid in tissues may be a major activator of inflammosomes and thus, it promotes damage to surrounding tissues 3 . In chronic liver disease, there is progressive damage to liver parenchyma with subsequent loss of function.…”

Section: Introductionmentioning

confidence: 99%

Study of Serum Uric Acid in Chronic Liver Disease and Its Relation With Other Parameters

Paul¹,

Chakravarti²,

Mandal³

et al. 2013

Int. Res. J. Pharm.

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In chronic liver disease, high uric acid levels are independently associated with severe disease and poor prognosis. However, studies regarding the relation of uric acid levels with different parameters of liver dysfunction are rare from India. Our aim was to study uric acid (UA) levels in chronic liver disease and find any association of UA with different blood parameters and prognosis. We selected patients of chronic liver disease of any etiology. We did the serum UA test along with full liver function tests. Child Turcot Pugh (CTP) score was calculated for each patient. Then by suitable statistical tests, any association or correlation was studied. We had total of 52 patients with 31 % female. 19 (36.5 %) of the cases had liver disease secondary to alcoholism followed by 15 cases of non alcoholic fatty liver disease. 69.2 % of the patients were in CTP class B or C. Serum UA levels were significantly higher in chronic viral hepatitis cases (p<0.001). UA levels showed significant correlation with serum bilirubin (r=0.567), SGOT (r=0.464) and mortality. The UA levels showed significant correlation with severe disease and mortality. However, whether UA can be included in risk stratification of chronic liver disease can only be determined by larger randomized trials.

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Uric Acid Is a Danger Signal Activating NALP3 Inflammasome in Lung Injury Inflammation and Fibrosis

Cited by 373 publications

References 54 publications

Inflammasome components Asc and caspase-1 mediate biomaterial-induced inflammation and foreign body response

Inflammasome components Asc and caspase-1 mediate biomaterial-induced inflammation and foreign body response

TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells

Study of Serum Uric Acid in Chronic Liver Disease and Its Relation With Other Parameters

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