Mobilization of classical monocytes from the bone marrow is under control of the CCR2CCCL2 axis111 and genetic deletion of greatly reduces atherosclerotic lesion sizes, likely due to monocytopenia in this model12,112. formation in atherosclerotic lesions of mice expressing or might benefit from an anti-IL-6 strategy warrants further investigation. Likewise, those with clonal haematopoiesis due to mutations in might benefit from administration of a JAK1/2 inhibitor such as ruxolitinib74,108. The use of biomarkers, including genetic variants, as a strategy for precision targeting of anti-inflammatory therapies could permit smaller, quicker and more economical end point studies that are ultimately needed to establish benefit and receive approval from regulatory authorities. Preclinical strategies Limiting arterial inflammation With the success of CANTOS, several strategies have emerged to interfere with IL-1 or its production, including inhibition of inflammasome activation. In addition, there are currently several promising avenues of research that have not yet entered the clinical trial phase but are in active development. In this section, Mps1-IN-3 we focus on selected aspects of controlling arterial inflammation and direct the reader to recent overview articles for broader information109,110. Closing the gates for myeloid cells A group of small chemotactic cytokines known as chemokines orchestrate immune cell trafficking. Upon binding to G-protein-coupled receptors, chemokines regulate immune cell movement in steady state as well as during inflammation. Given the importance of intimal leukocyte accumulation during atheroprogression, antagonizing chemokineCreceptor interactions may be a promising therapeutic avenue. Activated endothelial cells can release C-X-C motif chemokine 1 (CXCL1), which interacts with C-X-C chemokine receptor type 2 (CXCR2) on myeloid cells, thereby promoting mobilization from the bone marrow and recruitment to sites of inflammation, including the atherosclerotic lesion. Thus, genetic deletion of CXCR2 from bone marrow cells or antibody-mediated neutralization of CXCL1 reduces Mps1-IN-3 the atherosclerotic burden and lesional macrophage accumulation in mice12. Mobilization of classical monocytes from the bone marrow Mps1-IN-3 is under control of the CCR2CCCL2 axis111 and genetic deletion of greatly reduces atherosclerotic lesion sizes, likely due to monocytopenia in this model12,112. In myocardial infarction in mice, small interfering RNA (siRNA)-mediated silencing of CCR2 or delivery of a non-agonistic CCL2-competing mutant protein that exhibits strong proteoglycan binding lowered monocyte recruitment, ventricular remodelling and ischaemiaCreperfusion injury113,114 (Fig.?2a). In humans, higher plasma CCL2 levels are associated with a higher risk of cardiovascular events and higher lesional CCL2 associates with features of plaque destabilization115,116. Blocking CCR2 with an antibody that blocks CCL2 binding lowers CRP levels in patients at risk of cardiovascular disease117. Upon ligation of the chemokine receptor, a signalling cascade ensues that, in many cases, leads to integrin activation and, consequently, to cell adhesion. In atherosclerosis, platelets are KT3 Tag antibody a prominent source of CCL5, which, when immobilized on arterial endothelium, promotes monocyte adhesion and recruitment118. Consequently, lack of CCR5, a?receptor of CCL5, or inhibition of CCR5 with maraviroc, a?FDA-approved inhibitor of HIV entry, lowers the degree of atherosclerosis and lesional macrophage content in hypercholesterolaemic mice119,120. In a clinical setting, treatment of patients with HIV with maraviroc reduces atheroprogression121. Open in a separate window Fig. 2 Preclinical strategies to limit cardiovascular inflammation and stimulate its resolution.a | Reducing monocyte recruitment. Silencing of C-C chemokine receptor 2 (CCR2) or timed inhibition of CCR2 signalling reduces monocyte adhesion. Overriding chemokine receptor signalling, for example with the small molecule Ac2-26, reduces integrin activation and monocyte arrest. Heterodimers of C-C motif chemokine 5 (CCL5) and C-X-C motif chemokine 4 (CXCL4) as well as of CCL5 and neutrophil defensin 1 (DEFA1) promote monocyte adhesion. Small peptides that disrupt these interactions reduce monocyte adhesion during cardiovascular inflammation. b | Inhibiting neutrophil extracellular traps (NETs). Inhibition of protein-arginine deiminase type 4 (PAD4) halts NET release. DNase I cleaves DNA strands in NETs..
Categories