CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair

Abstract

Monocytes/macrophages are critical in orchestrating the tissue-repair response. However, the mechanisms that govern macrophage regenerative activities during the sequential phases of repair are largely unknown. In the present study, we examined the dynamics and functions of diverse monocyte/macrophage phenotypes during the sequential stages of skin repair. By combining the analysis of a new CCR2-eGFP reporter mouse model with conditional mouse mutants defective in myeloid cell–restricted CCR2 signaling or VEGF-A synthesis, we show herein that among the large number of inflammatory CCR2+Ly6C+ macrophages that dominate the early stage of repair, only a small fraction strongly expresses VEGF-A that has nonredundant functions for the induction of vascular sprouts. The switch of macrophage-derived VEGF-A during the early stage of tissue growth toward epidermal-derived VEGF-A during the late stage of tissue maturation was critical to achieving physiologic tissue vascularization and healing progression. The results of the present study provide new mechanistic insights into CCR2-mediated recruitment of blood monocyte subsets into damaged tissue, the dynamics and functional consequences of macrophage plasticity during the sequential repair phases, and the complementary role of macrophage-derived VEGF-A in coordinating effective tissue growth and vascularization in the context of tissue-resident wound cells. Our findings may be relevant for novel monocyte-based therapies to promote tissue vascularization.

Unraveling macrophage contributions to bone repair

“…These pro-angiogenic monocyte/macrophages had a mixed M1 and M2 profile. 48 Macrophages pervading the granulation tissue at a fracture site 12,29 are a confirmed cellular source of VEGFs in soft-tissue injury, 48 and VEGFs have been established as important proangiogenic molecules in fracture repair. 49 It remains to be definitively established whether macrophages direct vascularization within the granulation tissue during bone repair.…”

Macrophages – sensors and effectors coordinating skin damage and repair

“…Recently, our group examined the role of CCR2 in monocyte/ macrophage recruitment during skin wound healing [4]. A novel mouse model was generated that could either be used as CCR2-eGFP reporter mouse or for the myeloid cell-restricted deletion of the ccr2 gene [4]. The analysis of wound cell suspensions from CCR2-eGFP reporter mice by flow cytometry revealed a rapid accumulation of inflammatory CCR2 + Ly6C + monocytes/macrophages after skin injury.…”

“…The chemokine receptors CCR2 and CX 3 CR1 were identified as promising candidates to mediate monocyte recruitment and their functional impact on skin wound healing has been addressed in independent studies [31,32]. Recently, our group examined the role of CCR2 in monocyte/ macrophage recruitment during skin wound healing [4]. A novel mouse model was generated that could either be used as CCR2-eGFP reporter mouse or for the myeloid cell-restricted deletion of the ccr2 gene [4].…”

“…Adult mouse [16] Macrophages play critical roles in skeletal muscle regeneration Adult mouse [50,58] Macrophages exert specific roles at diverse stages of repair and orchestrate the natural sequence of repair phases in skin Adult mouse [4,[17][18][19] Gr-1 + CD11b + cells contribute to injury-induced neo-vascularization Adult mouse [42] Non-inflammatory Ly6C low MHCII high wound macrophages promote wound healing Adult mouse [43] Persisting pro-inflammatory macrophages impair wound healing in venous Ulcers Human [40] classical/alternative macrophage activation is operative at the cutaneous wound site and which of the micro-environmental cues may direct macrophage activation. Furthermore, the functional relation between the recruitment of diverse blood monocyte subtypes into damaged tissue and their potential activation to the alternative or classical macrophage phenotype was unclear.…”

“…The underlying mechanisms are not yet resolved but there is accumulating evidence that the inflammatory response plays a pivotal role directing the outcome of the healing response [3]. Macrophages represent one of the most abundant inflammatory cell types during all stages of tissue repair [4], exerting remarkable functional and phenotypic plasticity [5,6] (Figure 1). Their primary function upon recruitment from the blood into the site of the damaged tissue is to clear cellular debris and necrotic tissue.…”