Vascular Endothelial Growth Factor Receptor Type 1 Signaling Prevents Delayed Wound Healing in Diabetes by Attenuating the Production of IL-1β by Recruited Macrophages
Vascular Endothelial Growth Factor Receptor Type 1 Signaling Prevents Delayed Wound Healing in Diabetes by Attenuating the Production of IL-1β by Recruited Macrophages
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DOI：
10.1016/j.ajpath.2016.02.014
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发表时间：
2016-06-01
影响因子：
6
通讯作者：
Majima, Masataka
中科院分区：
文献类型：
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作者：
Okizaki, Shin-ichiro;Ito, Yoshiya;Majima, Masataka
促炎巨噬细胞被募集至肉芽组织，其持续存在会损害糖尿病伤口的愈合。在此，我们研究了血管内皮生长因子受体 1 型 (VEGFR1) 信号在链脲佐菌素 (STZ) 诱导的糖尿病伤口愈合中的作用。与媒介物治疗的 WT 小鼠相比，STZ 治疗的野生型 (WT) 小鼠的血管生成、淋巴管生成和全层皮肤伤口的愈合受到损害，表达血管内皮生长因子 (VEGF)-A、VEGF-C 和 VEGF-D 的 VEGFR1 阳性巨噬细胞向伤口肉芽组织的募集减弱。这些现象在 STZ 治疗的 VEGFR1 酪氨酸激酶敲除小鼠（VEGFR1 TK-/- 小鼠）中更为普遍。当用胎盘生长因子治疗时，STZ 治疗的 WT 小鼠（而非 STZ 治疗的 VEGFR1 TK-/- 小鼠）显示出加速的伤口愈合。与 STZ 治疗的 WT 小鼠相比，STZ 治疗的 VEGFR1 TK-/- 小鼠的伤口肉芽组织含有更多表达 IL-1 β（经典（M1）活化巨噬细胞标记物）的 VEGFR1 阳性细胞和更少表达甘露糖受体（CD206；CD206；替代激活（M2）巨噬细胞标记]。用 IL-1 β 中和抗体治疗 STZ 治疗的 VEGFR1 TK-/- 小鼠可恢复受损的伤口愈合和血管生成/淋巴管生成，并诱导伤口肉芽组织中的巨噬细胞转变为 M2 表型。综上所述，这些结果表明 VEGFR1 信号传导在调节 STZ 诱导的糖尿病伤口中巨噬细胞表型之间的平衡中发挥作用，防止糖尿病伤口愈合受损，并促进血管生成/淋巴管生成。
The persistence of proinflammatory macrophages, which are recruited to the granulation tissue, impairs the healing of diabetic wounds. Herein, we examined the role of vascular endothelial growth factor receptor type 1 (VEGFR1) signaling in streptozotocin (STZ)-induced diabetic wound healing. Angiogenesis, lymphangiogenesis, and the healing of full-thickness skin wounds were impaired in STZ-treated wild-type (WT) mice compared with vehicle-treated WT mice, with attenuated recruitment of VEGFR1-positive macrophages expressing vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D to the wound granulation tissue. These phenomena were even more prevalent in STZ-treated VEGFR1 tyrosine kinase knockout mice (VEGFR1 TK-/- mice). STZ-treated WT mice, but not STZ-treated VEGFR1 TK-/- mice, showed accelerated wound healing when treated with placenta growth factor. Compared with that of STZ-treated WT mice, the wound granulation tissue of STZ-treated VEGFR1 TK-/- mice contained more VEGFR1-positive cells expressing IL-1 beta [a classic (M1) activated macrophage marker] and fewer VEGFR1-positive cells expressing the mannose receptor [CD206; an alternatively activated (M2) macrophage marker]. Treatment of STZ-treated VEGFR1 TK-/- mice with an IL-1 beta-neutralizing antibody restored impaired wound healing and angiogenesis/lymphangiogenesis and induced macrophages in the wound granulation tissue to switch to an M2 phenotype. Taken together, these results suggest that VEGFR1 signaling plays a role in regulating the balance between macrophage phenotypes in STZ-induced diabetic wounds, prevents impaired diabetic wound healing, and promotes angiogenesis/lymphangiogenesis.