CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis

Abstract

Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non-foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163+ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1α and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1α via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163+ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1α/VEGF-A pathway.

Immune Profiling of Atherosclerotic Plaques Identifies Innate and Adaptive Dysregulations Associated with Ischemic Cerebrovascular Events

“…2e ). Remarkably, these differences were not driven by plaque pathology—as both prospectively enrolled ASYM and SYM patients of cohort 1 presented the same type VI plaque according to the American Heart Association (AHA) classification 47 —nor by their clinical characteristics ( Supplementary Information and Supplementary Fig. 2a-e ).…”

“…In particular, macrophages of MC 1 showed high expression of CD206 and CD163 ( Extended Fig. 2a ), markers of alternative M2-like macrophages in atherosclerotic tissue that have been associated with either atheroprotective or proatherogenic functions 46,47 . This analysis also revealed 9 MCs of T cells in plaques which comprised 3 subsets of CD8 + T cells (MCs 3, 7 and 10) and 5 of CD4 + T cells (MCs 5, 8, 9, 13 and 15) ( Extended Fig.…”

RACK1 promotes cancer progression by increasing the M2/M1 macrophage ratio via the NF‐κB pathway in oral squamous cell carcinoma

“…CD206, CD163 and CD204 are useful for M2 detection. Moreover, CD68 is considered a pan‐macrophage marker (Guo et al , ; Gustafson et al , ; Han et al , ; Motomura et al , ; Olesch et al , ; Salmi et al , ; Tan‐Garcia et al , ; Wang et al , ).…”

“…The most commonly used markers for M1 macrophages are CD11c, CD80 and HLA-DR. CD206, CD163 and CD204 are useful for M2 detection. Moreover, CD68 is considered a pan-macrophage marker (Guo et al, 2018;Gustafson et al, 2015;Han et al, 2016;Motomura et al, 2015;Olesch et al, 2015;Salmi et al, 2018;Tan-Garcia et al, 2017;Wang et al, 2014a).…”

Silencing of NONO inhibits abdominal aortic aneurysm in apolipoprotein E‐knockout mice via collagen deposition and inflammatory inhibition

“…Inflammation has been considered a key pathological feature in Ang II-induced AAA, characterized by enhanced inflammatory infiltration and release of pro-inflammatory cytokines. 29,30 Previous studies reported that NONO may play a part in the cAMP-signalling cascade to control its downstream inflammatory genes. 12,31 In this study, NONO silencing significantly reduced the accumulation of macrophages in AAA tissues and markedly reduced the manifestation levels of pro-inflammatory cytokines, comprising MCP-1, IL-6, IL-1β as well as TNF-α.…”