Oncostatin M receptor β deficiency attenuates atherogenesis by inhibiting JAK2/STAT3 signaling in macrophages

Oncostatin M (OSM) is a secreted cytokine mainly involved in chronic inflammatory and cardiovascular diseases through binding to OSM receptor beta (OSMR-beta). Recent studies demonstrated that the presence of OSM contributed to the destabilization of atherosclerotic plaque. To investigate whether OSMR-beta deficiency affects atherosclerosis, male OSMR-beta(-/-) ApoE beta(-/-) mice were generated and utilized. Here we observed that OSMR-beta expression was remarkably upregulated in both human and mouse atherosclerotic lesions, which were mainly located in macrophages. We found that OSMR-beta deficiency significantly ameliorated atherosclerotic burden in aorta and aortic root relative to ApoE-deficient littermates and enhanced the stability of atherosclerotic plaques by increasing collagen and smooth muscle cell content, while decreasing macrophage infiltration and lipid accumulation. Moreover, bone marrow transplantation of OSMR-beta(-/-) hematopoietic cells to atherosclerosisprone mice displayed a consistent phenotype. Additionally, we observed a relatively reduced level of JAK2 and signal transducer and activator of transcription (STAT) 3 in vivo and under Ox-LDL stimulation in vitro. Our findings suggest that OSMR-beta deficiency in macrophages improved high-fat diet-induced atherogenesis and plaque vulnerability.(jlr) Mechanistically, the protective effect of OSMR-beta deficiency on atherosclerosis may be partially attributed to the inhibition of the JAK2/STAT3 activation in macrophages, whereas OSM stimulation can activate the signaling pathway.