Activation of the Stimulator of Interferon Genes (STING) protein has paradoxical outcomes in skin disease. STING activation exacerbates psoriatic skin disease and delays wound healing in diabetic mice, yet it also facilitates wound healing in normal mice. To address the role of localized STING activation in the skin, mice were injected subcutaneously with a STING agonist, diamidobenzimidazole STING Agonist-1 (diAbZi). The effect of a prior inflammatory stimulus on STING activation was addressed by pre-treating mice intraperitoneally with poly (I:C). The skin at the injection site was evaluated for local inflammation, histopathology, immune cell infiltration, and gene expression. Serum cytokine levels were measured to assess systemic inflammatory responses. Localized diABZI injection induced severe skin inflammation with erythema, scaling, and induration. However, the lesions were self-limiting and resolved within 6 weeks. At the peak of inflammation, the skin showed epidermal thickening, hyperkeratosis, and dermal fibrosis. Neutrophils, CD3 T cells, and F4/80 macrophages were present in the dermis and subcutaneous layers. Gene expression was consistent with increased local interferon and cytokine signaling. Interestingly, the poly (I:C)-pre-treated mice showed higher serum cytokine responses and developed worse inflammation with delayed wound resolution. Our study demonstrates that prior systemic inflammation amplifies STING-mediated inflammatory responses and skin disease.

The activation of the stimulator of interferon genes 1 (Sting1) pathway causes rapid induction of type I IFNs. Recently, different STING agonists are being proposed as therapeutics for controlling viral infections like those caused by the SARS-CoV-2. Considering that excessive STING activation leads to autoimmunity, this study was undertaken to investigate the effects of STING activation under pre-existing systemic inflammatory conditions induced by a viral infection. Female BALB/c mice were treated (Tx) with TLR3 agonist poly(IC), which was followed 24h later by subcutaneous injection of STING agonist diamidobenzimidazole (diAbZi). Only diAbZi or vehicle Tx mice were used as controls. Mice Tx with poly(IC) and diAbZi showed the highest systemic levels of type I IFNs, IL-6, and TNFα. Within 10 days, the salivary glands showed increased ILC1, monocytes, and CD8+ T cells. However, glandular function was not affected. Five days after Tx, except for the vehicle controls, all mice showed differing extents of redness, hair loss, and ulceration at the injection site. By day 10, diABZi alone Tx mice showed either normal skin or a small scar formation. In contrast, mice Tx with poly IC and diABZi, showed extensive hair loss, erythema, and ulceration. In addition, hematoxylin and eosin-stained skin sections showed extensive neutrophilic infiltration at the site of ulceration, epidermal thickening, and patchy lymphocytic infiltrate that extended into the subdermal layers. Our data demonstrate that STING activation under systemic inflammatory conditions, such as a viral infection, can lead to severe skin disease. Therefore, caution needs to be exercised in employing STING agonists as therapeutics for treating SARS-CoV-2.