Knockdown of GSDMD inhibits pyroptosis in psoriasis by blocking the NOD-like receptor signaling pathway.

BACKGROUND

Psoriasis is a chronic inflammatory skin disease regulated by autoimmunity, and pyroptosis plays an important role in this condition. This research sought to examine the function and potential molecular pathway of Gasdermin D (GSDMD) in psoriasis.

METHODS

GSDMD expression was examined by immunohistochemistry in biopsied skin tissues from patients with psoriasis. Pyroptosis-related genes and inflammatory factors were quantified using qRT-PCR and ELISA, respectively. HaCaT cells were treated with M5 cytokines to develop an in vitro psoriasis model, while imiquimod (IMQ) was administered to construct an in vivo psoriasis model. To counteract the inhibition of the NOD-like receptor (NLR) pathway caused by GSDMD knockdown, the pathway activator M-TriDAP was employed.

RESULTS

In the lesional skin tissues of patients with psoriasis, GSDMD expression was highly expressed. The levels of pro-pyroptosis mediators were increased, whereas the level of anti-inflammatory factor was lowered. GSDMD knockdown and disulfiram treatment inhibited pyroptosis and promoted apoptosis in M5-induced HaCaT cells. In the IMQ-induced psoriasis-like mouse model, GSDMD knockdown suppressed pyroptosis and improved skin lesion severity, alleviating erythema, epidermal thickness, and inflammatory cell infiltration. Mechanistically, GSDMD knockdown inhibited the NLR pathway, accompanied by reduced protein levels of NLRP3, NOD1, NOD2, and PYCARD. NLR pathway activator, M-TriDAP treatment significantly reversed the effects of GSDMD knockdown on psoriasis progression.

CONCLUSIONS

Knockdown of GSDMD inhibits pyroptosis in psoriasis by blocking the NLR signaling pathway, presenting a novel potential strategy for psoriasis treatment.