Extramedullary Hematopoiesis Generates Ly-6C ^high Monocytes That Infiltrate Atherosclerotic Lesions

Abstract

Background Atherosclerotic lesions are believed to grow via the recruitment of bone marrow-derived monocytes. Among the known murine monocyte subsets, Ly-6Chigh monocytes are inflammatory, accumulate in lesions preferentially, and differentiate. Here we hypothesized that the bone marrow outsources the production of Ly-6Chigh monocytes during atherosclerosis. Methods and Results Using murine models of atherosclerosis and fate-mapping approaches, we show that hematopoietic stem and progenitor cells (HSPC) progressively relocate from the bone marrow to the splenic red pulp where they encounter GM-CSF and IL-3, clonally expand, and differentiate to Ly-6Chigh monocytes. Monocytes born in such extramedullary niches intravasate, circulate, and accumulate abundantly in atheromata. Upon lesional infiltration, Ly-6Chigh monocytes secrete inflammatory cytokines, reactive oxygen species, and proteases. Eventually, they ingest lipids and become foam cells. Conclusions Our findings indicate that extramedullary sites supplement the bone marrow’s hematopoietic function by producing circulating inflammatory cells that infiltrate atherosclerotic lesions.

Microglia and Monocyte-Derived Macrophages in Stroke

“…While monocytes are also formed in the liver and spleen [70][71][72], the view that monocytes are derived from the bone marrow has been established since the early 1960s and still dominates [73]. The monocytes produced from the bone marrow exit to the circulatory system in a C-C chemokine receptor 2 (CCR2)-dependent manner and enter tissues to give rise to tissue macrophages [74].…”

Monocytes and Macrophages in Cancer: Development and Functions

“…Still, monocytes are also produced by extra-medullary hematopoiesis in the spleen and increase under inflammatory conditions such as atherosclerosis and cancer as recently shown [9,10]. In the bone marrow, monocytes are generated from HSC in a sequential process of differentiation and commitment steps [3,11], collectively called monopoiesis (Fig.…”

Nanoparticle-Mediated Delivery of Pitavastatin to Monocytes/Macrophages Inhibits Left Ventricular Remodeling After Acute Myocardial Infarction by Inhibiting Monocyte-Mediated Inflammation

“…6) Immediately after MI, monocytes in the splenic reservoir are mobilized to the infarcted myocardium via activation of the angiotensin II type 1 receptor 7) and then, bone marrow-derived monocytes accumulate by MCP1-CCR2-mediated mechanisms. 8,9) Monocytes accumulating in the infarcted heart consist of at least two phases: accumulation of Ly-6C high(hi) inflammatory monocytes (CD14 ++ CD16 -monocytes in humans) immediately after MI and Ly-6C low(lo) reparative monocytes (CD14 + CD16 ++ monocytes in humans) in the later phase. 10) In humans, it was recently reported that the CD14 ++ CD16 + "intermediate" subset of monocytes is also associated with LV remodeling after AMI in diabetic patients.…”