Blood vessel control of macrophage maturation promotes arteriogenesis in ischemia

Abstract

Ischemia causes an inflammatory response that is intended to restore perfusion and homeostasis yet often aggravates damage. Here we show, using conditional genetic deletion strategies together with adoptive cell transfer experiments in a mouse model of hind limb ischemia, that blood vessels control macrophage differentiation and maturation from recruited monocytes via Notch signaling, which in turn promotes arteriogenesis and tissue repair. Macrophage maturation is controlled by Notch ligand Dll1 expressed in vascular endothelial cells of arteries and requires macrophage canonical Notch signaling via Rbpj, which simultaneously suppresses an inflammatory macrophage fate. Conversely, conditional mutant mice lacking Dll1 or Rbpj show proliferation and transient accumulation of inflammatory macrophages, which antagonizes arteriogenesis and tissue repair. Furthermore, the effects of Notch are sufficient to generate mature macrophages from monocytes ex vivo that display a stable anti-inflammatory phenotype when challenged with pro-inflammatory stimuli. Thus, angiocrine Notch signaling fosters macrophage maturation during ischemia.

<p>Functional aspects, phenotypic heterogeneity, and tissue immune response of macrophages in infectious diseases</p>

“…220 Macrophages are found in both blood and tissues, and despite their common origin in the bone marrow, tissue macrophages appear to exhibit an embryogenic development that is independent of that of blood macrophages or even of macrophages that migrate from the blood into tissues. [221][222][223] Macrophages perform a wide spectrum of functions in various tissues, including the removal of dead cells, as well as tissue remodeling and repair, which are associated with an elaborate response to foreign agents and infectious or noninfectious aggressors. [224][225][226] Given this, macrophages are crucial for the development of the organ-specific immune response, which acts on innate and adaptive immunity, frequently serving as a bridge between these two types of responses.…”

Isoform-Specific Roles of ERK1 and ERK2 in Arteriogenesis

“…While angiogenesis involves simple proliferation and sprouting of capillary endothelial cells, arteriogenesis requires a coordinated response that involves multiple cell types that, in addition to endothelial and vascular smooth muscle cells, include a panoply of inflammatory cells including lymphocytes [8,9], natural killer cells [10], macrophages [11], and mast cells [12]. The presence of inflammatory cells (and a local inflammatory response at an arteriogenic site) is critical as these cells serve as the major source of VEGF in the absence of tissue ischemia [13][14][15][16][17].…”

Circulating delta-like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus-based immunosuppression

“…5 The Notch signaling pathway is essential for communication between neighboring cells 9 and processes known to contribute to CAV, 10 like EC activation, 11 accumulation and activation of immune cells, 12 proliferation of VSMCs, extracellular matrix (ECM) remodeling 13,14 and T cell activation. 17 The canonical delta-like Notch ligand 1 (DLL1) regulates the cell fate of monocytes, 18 macrophages, 19 T cells, 20 and ECs, 21 and in HF, circulating DLL1 is elevated and associated with impaired cardiac function and adverse outcome. 16 Proteolysis induces secretion of extracellular domains, which together with a large group of noncanonical ligands may modulate Notch signaling.…”

“…16 Proteolysis induces secretion of extracellular domains, which together with a large group of noncanonical ligands may modulate Notch signaling. 17 The canonical delta-like Notch ligand 1 (DLL1) regulates the cell fate of monocytes, 18 macrophages, 19 T cells, 20 and ECs, 21 and in HF, circulating DLL1 is elevated and associated with impaired cardiac function and adverse outcome. 22,23 To our knowledge, DLL1 is the only detectable canonical Notch ligand in human plasma/serum.…”