The STING antagonist H‐151 ameliorates psoriasis via suppression of STING/NF‐κB‐mediated inflammation

Abstract

Background and Purpose: Psoriasis is a chronic inflammatory skin disease associated with both innate and adaptive immune responses. The stimulator of interferon genes (STING) protein engages in sensing of cytosolic DNA to initiate dsDNA-driven immune responses. In vitro and in vivo anti-psoriasis effects of STING antagonist H-151 were explored.Experimental Approach: We analysed the gene expression profile of STING and related downstream targets in the skin samples of healthy people and psoriasis patients from the GEO database. Cellular inhibitory activity of H-151 on STING pathway was confirmed via qPCR and western blotting. The preventive effect of topical application of H-151 on imiquimod-induced psoriatic mice was examined through histological, immunohistochemical, immunofluorescent, flow cytometric analysis, ELISA Kits and other approaches. Preliminary mechanistic studies were also performed.Key Results: Gene expressions of STING and its downstream target were upregulated in lesional skin samples from psoriasis patients. Topical administration of H-151 attenuated the skin lesions in imiquimod-induced psoriatic mouse model, while the secretion of pro-inflammatory cytokines (IL-17, IL-23 and IL-6), infiltration of M1 macrophages and differentiation of Th17 cells were significantly suppressed by H-151 treatment. Mechanistically, H-151 inhibited STING/NF-κB signalling in both keratinocytes and immune cells. Conclusion andImplications: H-151 displayed anti-inflammatory activity in both keratinocytes and immune cells, and decreased the severity of psoriatic response in vivo. Inhibition of STING signalling pathway may represent a novel therapeutic approach to psoriasis and related complications.

Intervention of cGAS‒STING signaling in sterile inflammatory diseases

“…Moreover, a series of nitrofuran derivatives, including C-176, C-178, and H-151, have been identified through a cell-based chemical screen, which covalently target STING at Cys91 and block the activation-induced palmitoylation of STING ( Haag et al., 2018 ). These compounds have been widely evaluated in disease models and proved to be effective in ameliorating multiorgan inflammation in AGS, ALS, Niemann–Pick disease type C, chronic kidney disease, and psoriasis ( Haag et al., 2018 ; Chung et al., 2019 ; Yu et al., 2020 ; Chu et al., 2021b ; Pan et al., 2021 ). Notably, C-176 and C-178 are specific mouse STING inhibitors, while H-151 inhibits both mouse and human STING activation.…”

What role of the cGAS-STING pathway plays in chronic pain?

“…STING activation can trigger nuclear factor κB (NF-κB) signaling to mediate immune defense against tumors and viral infections (Yum et al, 2021 ). Simultaneously, STING antagonist H-151 has been shown that suppresses STING/NF-κB-mediated inflammation to ameliorate psoriasis (Pan et al, 2021 ). Notably, the latest research in neuropathic pain has indicated that STING may activate the NF-κB and release the proinflammatory cytokines IL-6 in the spinal cord to aggravate chronic pain.…”

“…The intrinsic self-dsDNA may activate cGAS-STING in chronic pain Furthermore, extrinsic dsDNA and intrinsic dsDNA can activate cGAS-STING pathway and induce chronic pain. For example, self-dsDNA was increased and mediated the activation of cGAS-STING pathway in the spinal cord, contributing to the spared nerve injury (SNI)-induced neuropathic pain (Sun et al, 2021). The intrinsic self-dsDNA is composed of nDNA and mtDNA, which can be segregated inaccurately and released into the cytosol, triggering the STING pathway (Bhattacharya et al, 2017).…”

“…Notably, the latest research in neuropathic pain has indicated that STING may activate the NF-κB and release the proinflammatory cytokines IL-6 in the spinal cord to aggravate chronic pain. However, injecting STING antagonist C-176 can provide an analgesic effect and reverse the increased expression of NF-κB (Sun et al, 2021). Additionally, NF-κB is a transcription factor for various cytokines, including CX3CL1, IL-1β, IL-6, and TNF-α, to induce peripheral and central sensitization in chronic pain (Sun et al, 2012;Liu et al, 2018;Xiang et al, 2019;Li Y. et al, 2020;Xu et al, 2021).…”

“…Concerning the roles of the cGAS-STING pathway in chronic pain, it has been reported that activating the cGAS-STING may have various effects. Some studies indicated that STING releases proinflammatory cytokines, which may cause neuroinflammation to aggravate chronic pain (Wang et al, 2019;Tian et al, 2020;Sun et al, 2021). In contrast, another study showed that type 1 interferons over-activated by cGAS-STING pathway might exert an antinociceptive effect in sensory neurons (Donnelly et al, 2021).…”