Sindrilaru Anca, Scharffetter-Kochanek Karin
Department of Dermatology and Allergic Diseases, University of Ulm , Ulm, Germany .
Adv Wound Care (New Rochelle). 2013 Sep;2(7):357-368. doi: 10.1089/wound.2012.0407.
Macrophages are invariably present and tightly regulate all phases of adult wound healing, including inflammation, granulation tissue formation, and matrix deposition with the unavoidable outcome of scar formation. In response to environmental cues, macrophages mount a "classical" pro-inflammatory M1 activation as opposed to the "alternative" M2 phenotype, with wound macrophages having long been viewed as M2 macrophages.
Recent studies rather point to large temporal and phenotypic variations of wound macrophages subsets. Therefore, a functional classification of macrophages according to wound-healing phases appears to better meet the complexity. In an ideal but simplistic scenario grossly reflecting normal wound healing, initial tissue injury induces inflammatory M1-like macrophages, which, upon engulfment of apoptotic neutrophils or in response to other inflammation dampening stimuli, switch toward anti-inflammatory M2-like macrophages and further toward growth factor-producing pro-fibrotic M2a-like macrophages. Although not yet documented for skin wounds, a subset of metalloproteinase-producing fibrolytic M2c-like macrophages may contribute to fibrosis resolution. Recent work identified a diversity of novel macrophage phenotypes associated with normal and pathologic wound healing, most of them ranging out of the M1/M2 paradigm. Iron-overloaded M1-like macrophages represent such a novel phenotypic subset driving the non-healing state of chronic venous leg ulcers.
Despite growing evidence that macrophage dysfunctions are, at least in part, responsible for pathologic wound healing, including nonhealing wounds and excessive scar formation, these are hardly specifically addressed even by modern therapeutic strategies.
If characterized in sufficient detail, distinct macrophage subsets and their impaired functions provide ideal targets for improving wound healing.
巨噬细胞始终存在，并严格调控成人伤口愈合的各个阶段，包括炎症、肉芽组织形成和基质沉积，不可避免地会形成瘢痕。巨噬细胞会根据环境信号进行“经典”的促炎M1活化，而非“替代”的M2表型，长期以来伤口巨噬细胞一直被视为M2巨噬细胞。
近期研究表明伤口巨噬细胞亚群存在较大的时间和表型差异。因此，根据伤口愈合阶段对巨噬细胞进行功能分类似乎更能应对这种复杂性。在一个大致反映正常伤口愈合的理想但简单的情景中，初始组织损伤会诱导出炎症性M1样巨噬细胞，这些巨噬细胞在吞噬凋亡中性粒细胞或对其他炎症抑制刺激作出反应后，会转变为抗炎性M2样巨噬细胞，并进一步转变为产生生长因子的促纤维化M2a样巨噬细胞。虽然皮肤伤口尚未有相关记录，但产生金属蛋白酶的促纤溶M2c样巨噬细胞亚群可能有助于纤维化的消退。近期研究发现了多种与正常和病理性伤口愈合相关的新型巨噬细胞表型，其中大多数超出了M1/M2范式。铁过载的M1样巨噬细胞就是这样一种新型表型亚群，它导致慢性下肢静脉溃疡处于不愈合状态。
尽管越来越多的证据表明巨噬细胞功能障碍至少在一定程度上导致了病理性伤口愈合，包括伤口不愈合和过度瘢痕形成，但即使是现代治疗策略也几乎没有专门针对这些问题。
如果能得到足够详细的表征，不同的巨噬细胞亚群及其受损功能将为改善伤口愈合提供理想的靶点。
