STING Gain-of-Function in Endothelial Cells Impairs Wound Healing Responses

Abstract

STimulator of Interferon Genes (STING) gain-of-function (GOF) mutations, resulting in constitutive STING activation, have been linked to a rare autoinflammatory disease called STING-Associated Vasculopathy with onset in Infancy (SAVI). SAVI patients present with hallmark skin findings, including chilblains (cold-sensitive lesions on acral surfaces) and progressive ulcerative lesions. We used a murine model of SAVI, STING(V154M/WT)-(VM), to explore the impact of the VM mutant on wound repair using ultraviolet B (UVB) irradiation as a tool for skin injury.

Following UVB-induced injury, we found that VM mice developed exacerbated skin inflammation that persisted for 21 days or more. Conversely, WT mice developed mild erythema and erosion, which resolved within 7 days. Despite a strikingly different phenotype, total immune cell infiltration in VM skin was the same as WT within the first 5 days post-UVB irradiation. However, there were differences in the immune composition, including a significant lack of macrophage expansion during healing in VM skin.

Further, we discovered that the VM phenotype is independent of T-cell responses and type 1 interferon signaling, challenging prior expectations in the literature. To identify the cellular driver(s) of skin disease, we used busulfan chimera and conditional knock-in mouse models. We determined that STING GOF in endothelial cells was sufficient to induce ulcerative lesions in VM mice. The critical finding in this thesis work is that following UVB-induced skin injury, STING GOF mutation in endothelial cells prevented macrophage expansion and impaired wound healing responses.