Inflammasome Activation of Cardiac Fibroblasts Is Essential for Myocardial Ischemia/Reperfusion Injury

Abstract

Background-Inflammation plays a key role in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury; however, the mechanism by which myocardial I/R induces inflammation remains unclear. Recent evidence indicates that a sterile inflammatory response triggered by tissue damage is mediated through a multiple-protein complex called the inflammasome. Therefore, we hypothesized that the inflammasome is an initial sensor for danger signal(s) in myocardial I/R injury. Methods and Results-We demonstrate that inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes, is crucially involved in the initial inflammatory response after myocardial I/R injury. We found that inflammasomes are formed by I/R and that its subsequent activation of inflammasomes leads to interleukin-1␤ production, resulting in inflammatory responses such as inflammatory cell infiltration and cytokine expression in the heart. In mice deficient for apoptosis-associated speck-like adaptor protein and caspase-1, these inflammatory responses and subsequent injuries, including infarct development and myocardial fibrosis and dysfunction, were markedly diminished. Bone marrow transplantation experiments with apoptosis-associated speck-like adaptor protein-deficient mice revealed that inflammasome activation in bone marrow cells and myocardial resident cells such as cardiomyocytes or cardiac fibroblasts plays an important role in myocardial I/R injury. In vitro experiments revealed that hypoxia/reoxygenation stimulated inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes, and that hypoxia/reoxygenation-induced activation was mediated through reactive oxygen species production and potassium efflux. Conclusions-Our results demonstrate the molecular basis for the initial inflammatory response after I/R and suggest that the inflammasome is a potential novel therapeutic target for preventing myocardial I/R injury. (Circulation. 2011;123:594-604.)Key Words: cytokine Ⅲ heart Ⅲ hypoxia Ⅲ inflammation Ⅲ leukocyte I ncreasing evidence indicates that inflammation is involved in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury. 1 One prominent and early mediator for inflammation in I/R injury is interleukin-1␤ (IL-1␤). 2,3 I/R induces IL-1␤ expression in the heart, and the inhibition of IL-1␤ prevents myocardial injury after I/R, 3 suggesting that the deleterious effects of myocardial I/R are mediated, at least in part, by IL-1␤. In the generation of IL-1␤, pro-IL-1␤, an inactive precursor, undergoes proteolysis by the converting enzyme caspase-1. Caspase-1 is activated within a cytosolic multiprotein complex, the inflammasome. The inflammasome contains cytoplasmic receptors of the NACHT leucine-rich-repeat protein family that are associated with the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which in turn recruits and activates caspase-1. 4,5 Increasing evidence indicates that several sterile inflammatory responses triggered by tissue damage are mediated by th...

Role of the inflammasome in inflammatory responses and subsequent injury after hepatic ischemia-reperfusion injury

“…We favor the idea that different TLRs and inflammasome components may operate at distinct stages and in different cell types during hepatic IRI. 2 In support of our in vivo findings, we 2212 CORRESPONDENCE HEPATOLOGY, December 2013…”

Naoxintong attenuates Ischaemia/reperfusion Injury through inhibiting NLRP3 inflammasome activation

“…The ischemic heart exhibited enhanced inflammasome activation as demonstrated by increased caspase‐1 activity and increased IL‐1β production 4, 6, 14. In particular, IL‐1β is a prominent and early mediator for inflammation in myocardial I/R injury 15.…”

“…It is to note, although we demonstrated that the protective effects of NXT might be mediated by inhibition of pro‐inflammatory factor NLRP3 in our model, genetic silence of NLRP3 gene failed to show a similar cardiac protection under the same I/R challenge as shown in Figure 1C group PBS+I/R in this study, while previous studies demonstrated conflicting results and Kawaguchi et al . reported that genetic deletion of NLRP3 gene protects animal heart from challenges including I/R 6, while Sandanger et al . showed that the NLRP3 inflammasome activation during myocardial I/R is cardioprotective 37.…”

“…Increasing evidence also indicates that a sterile inflammatory response triggered by tissue damage is mediated through a multiple‐protein complex called the inflammasome 4, 5. It is known that nucleotide‐binding oligomerization domain‐Like Receptor with a Pyrin domain 3 (NLRP3) inflammasome are formed after myocardial I/R injury and the subsequent activation process could lead to the interleukin‐1β production 6, 7, which crucially contributes to cardiac ischaemia injury and post‐infarct remodelling.…”

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

“…CF express NLRP3 [73,76] and studies on ASC and caspase-1 knockout mice have revealed an essential role for the inflammasome in fibroblasts, but not cardiomyocytes, in the initial inflammatory response to myocardial ischaemia/reperfusion injury [131]. Furthermore, NLRP3 in CF has been shown to be important for producing IL-1 in response to extracellular ATP from damaged cardiomyocytes [73].…”