The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia–reperfusion injury

Abstract

This study shows that the NLRP3 inflammasome is up-regulated in myocardial fibroblasts post-MI, and may be a significant contributor to infarct size development during ischaemia-reperfusion.

NLRP3 Inflammasome as a Novel Player in Myocardial Infarction

“…18) They also showed that cardiomyocytes formed NLRP3 infl ammasome assembly and that its activation ultimately induced caspase-1-dependent cardiomyocyte cell death, known as pyroptosis, but not IL-1β release (Figure 3). The pathophysiologic role of the NLRP3 infl ammasome was also confirmed by Sandanger, et al 33) who reported that the NLRP3 infl ammasome was predominantly upregulated in the cardiac fi broblasts of the ischemic myocardium in murine and rat permanent MI models. They further showed that cardiac fibroblasts secreted IL-1β in response to ATP, which is released extracellularly by tissue damage during MI.…”

The role of P2X7 receptors in tissue fibrosis: a brief review

“…In accordance, results suggested that P2X 7 R activity was present in animal models of liver injury and fibrosis, and contributed to fibrogenesis [71,72]. Finally, it has been demonstrated that P2X 7 R may be a potential target for the treatment of pancreatic [79,80] and cardiac fibrosis [86,87]. Although the precise mechanism underlying the involvement of P2X 7 R in fibrosis remains unclear and requires further investigation, the receptor seems to be a nodal point in fibrogenesis as an integral component of a pro-inflammatory mechanism.…”

“…In addition, they showed that the prevention of inflammasome assembly using a pharmacological P2X 7 R inhibitor, pyridoxalphosphate-6′-azopheny-2′, 4′-disulphonate (PPADS), reduces cell death and adverse cardiac remodeling. The direct implication of the P2X 7 R and the upregulation of the NLRP3 inflammasome in CF have been shown in a recent study conducted in mice following myocardial ischaemia-reperfusion (I/R) injury [87] in which silencing P2X 7 R in vivo with siRNA has revealed a reduction of the infarct size after myocardial infarction. In keeping with these findings, in vitro data show that myocardial fibroblasts release IL-1β and IL-18 when primed with LPS and subsequently exposed to the danger signal ATP, a molecule that is released in relation to tissue damage during myocardial infarction [87].…”

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

“…At the cellular level, isolated rat and mouse cardiomyocytes express TLR2, 3, 4 and 6 [71,72], but TLR expression in fibroblasts is less well characterised. However, there is evidence for functional expression of TLR2 [57,73], TLR3 [73], TLR4 [68,73,74] and TLR9 [73,75] in CF. Of the known members of the NLR family, CF express NOD1 and NOD2 [26,62], as well as the inflammasome-associated NLRP3 [73,76] RAGE is expressed in several cell types within the heart [64] and in cultured human and rodent CF [23,[77][78][79].…”

“…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]. A pivotal role for the NLRP3 inflammasome in CF for induction of myocardial dysfunction in sepsis has also recently been reported [132].…”