Abstract 398: Impaired Macrophage Interleukin-1β-Dependent Wound Healing In The Context Of Diabetes

Abstract

Peripheral Artery Disease (PAD), associated with diabetes, is an atherosclerotic vascular disease with impaired angiogenesis and poor wound healing. Increasing data support early inflammation as playing a key role in setting the state for adequate recovery following acute vascular injury. Here, we sought to understand the impact of diabetes upon IL-1β-dependent angiogenesis during wound healing. We identified an important role for inflammatory macrophage IL-1β-driven vascular endothelial growth factor-A (VEGF-A) production during angiogenesis required for wound healing. To determine the role of IL-1β signaling in the context of diabetes, we used a macrophage-specific IL-1 β -deletion model ( mIL-1 β ), a macrophage-specific IL-1R -deletion model ( mIL-1R ), and a Leptin ( Lepr db/db ) model. Using a punch biopsy model, wound closure was quantified over ten days. Mice with diabetes ( Lepr db/db ) demonstrate initial wound expansion, followed by delayed wound closure. Comparable results were found using mIL-1 β mice, suggesting that mice with diabetes may phenocopy disrupted IL-1β signaling. Analysis from all three models confirmed decreased macrophage expression of pro-angiogenic VEGF-A in response to IL-1β signaling in vitro and reduced VEGF-A expression in wounds in vivo . We examined the impact of upregulating IL-1β-dependent transcription factors, STAT3 and NF-κB, to bypass the impairment conferred by diabetes and found that constitutively active STAT3 and IKK-2 (NF-κB activator) appear to reconstitute VEGF-A expression in macrophages. In summary, angiogenesis dependent healing requires the contribution of macrophage IL-1β-dependent VEGF-A expression in the early inflammatory state, and diabetes is associated with an impairment in this pathway. Therapeutic angiogenesis strategies in the context of diabetes may require upregulation of transcription factors downstream of IL-1β to restore macrophage VEGF-A expression that is required for angiogenesis-dependent wound healing.