p38δ MAPK

Abstract

Objective— Activation of the inflammasome pathway in macrophages results in the secretion of 2 potent proinflammatory and proatherogenic cytokines, interleukin (IL)-1β, and IL-18. Atherosclerotic lesions are characterized by the presence of various endogenous activators of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, including cholesterol crystals and extracellular ATP. The aim of this study was to comprehensively characterize the expression of inflammasome pathway components and regulators in human atherosclerotic lesions. Approach and Results— Twenty human coronary artery RNA samples from 10 explanted hearts were analyzed using an inflammasome pathway–focused quantitative polymerase chain reaction array. Advanced atherosclerotic plaques, when compared with early-to-intermediate lesions from the same coronary trees, displayed significant upregulation of 12 target genes, including the key inflammasome components apoptosis-associated speck-like protein containing a CARD domain, caspase-1, and IL-18. Immunohistochemical stainings of the advanced plaques revealed macrophage foam cells positive for NLRP3 inflammasome components around the necrotic lipid cores. The polymerase chain reaction array target p38δ mitogen-activated protein kinase was upregulated in advanced plaques and strongly expressed by lesional macrophage foam cells. In cultured human monocyte–derived macrophages, the p38δ mitogen-activated protein kinase was activated by intracellular stress signals triggered during ATP- and cholesterol crystal–induced NLRP3 inflammasome activation and was required for NLRP3-mediated IL-1β secretion. Conclusions— Increased expression of the key inflammasome components in advanced coronary lesions implies enhanced activity of the inflammasome pathway in progression of coronary atherosclerosis. The p38δ mitogen-activated protein kinase was identified as a novel regulator of NLRP3 inflammasome activation in primary human macrophages, and thus, represents a potential target for modulation of atherosclerotic inflammation.

NLRP3 Inflammasome as a Molecular Marker in Diabetic Cardiomyopathy

“…Pyroptosis has been found in response to infection with several bacteria and viruses (Allen et al, 2009; Bergsbaken et al, 2009). However, aberrant or excessive activation of the NLRP3 inflammasome contribute to development of autoimmune and even metabolic diseases, such as type 2 diabetes (Donath and Shoelson, 2011), atherosclerotic disease (Rajamaki et al, 2016; Wang et al, 2017), obesity (Ahmad et al, 2016), gouty Arthritis (Liu Y. F. et al, 2016; Table 1). Recently, we and other researchers reported that pyroptosis were involved in non-infectious disease, such as atherosclerosis and DCM (Luo et al, 2014b; Wree et al, 2014).…”

Cell Death in the Vessel Wall

“…Endothelial activation, inflammation and early atherosclerosis in Apoe−/− is subsequently inhibited by the deletion of caspase-1, which confirms earlier reports that caspase-1 plays a key role in vascular disease progression 47–49 . In human macrophages, p38δ-MAPK is necessary for the activation of caspase-1 via the NLRP3 inflammasome and is upregulated in advanced but not early human atherosclerotic plaques 50 . Although many of these studies do not dissect the precise contribution of the pro-death versus pro-inflammatory roles for caspase-1, they underscore the potential importance of caspase-1 regulation as a key determining factor in the inflammation that drives atherosclerosis.…”

New Insights into the Mechanisms of Pyroptosis and Implications for Diabetic Kidney Disease

“…Furthermore, ROS inactivate phosphatase and tensin homolog, leading to PI3K and extracellular signal-regulated kinase (ERK) pathway stimulation in the upstream of pyroptosis. ROS can also activate NLRP3 inflammasome via p38MAPK signalling pathway and NF-κB pathway [ 46 , 47 , 52 ]. Supporting this prediction, recent studies revealed that NF-κB pathway elicited GSDMD-mediated pyroptosis in DKD mice’s tubular cells.…”