MCC950 protects retinal photoreceptor cells against blast-induced injury by inhibiting the NLRP3/Caspase-1/GSDMD pathway in mice

Blast-induced traumatic brain injury (bTBI) is frequently observed in industrial accidents and military operations, and presents unique mechanisms of injury and complex pathological evolution distinct from conventional ocular trauma when complicated by visual dysfunction. By investigating the effects of NLRP3 inhibitor MCC950 on retinal structure and function following blast wave exposure.

A bTBI mouse model was established using a biological shock tube. Male C57BL/6J mice (8 weeks old, weighing 23. 5±1. 5 g) were stratified by body mass and randomly divided into a sham group, a bTBI 28 d group, a bTBI 28 d+DMSO group, and a bTBI 28 d + MCC950 group (MCC950, 10 mg/kg, i. p.), with 8 animals in each group. After blast exposure, retinal function was evaluated by electroretinography (ERG, n=8); the protein levels of NLRP3, Caspase-1, Cleaved-GSDMD, IL-1β and IL-18 in the retina were detected by Western blotting (n=3); the activation of Müller cells and microglia was analyzed by immunofluorescence staining (IF) and Western blotting (n=3); and photoreceptor ultrastructural changes were observed with transmission electron microscopy (TEM, n=3).

Compared with the sham group, the bTBI 28 d group exhibited progressive visual dysfunction, manifested by significantly reduced amplitudes of the a-wave (P<0. 001), b-wave (P<0. 01), and oscillatory potentials (OPs) wave (P<0. 001) in dark-adapted ERG; significant activation of Müller cells (P<0. 05) and microglia (P<0. 001) in the retina; and significant elevated retinal protein levels of NLRP3 (P<0. 05), Caspase-1 (P<0. 01), Cleaved-GSDMD (P<0. 05), and downstream inflammatory factors IL-1β(P<0. 01) and IL-18 (P<0. 001). TEM revealed disorganized outer segment disc structures and inner segment vacuolization in photoreceptors of the bTBI 28 d group. MCC950 intervention significantly reversed these changes, as evidenced by significantly increased amplitudes of the a-wave, b-wave, and OPs wave in ERG in the bTBI 28 d+MCC950 group compared with the bTBI 28 d group (P<0. 05), significantly inhibited activation of Müller cells (P<0. 01) and microglia (P<0. 05), significant downregulation of pyroptosis pathway proteins including NLRP3, Caspase-1, Cleaved-GSDMD, IL-1β, and IL-18 (P<0. 01), and markedly attenuated photoreceptor ultrastructural damage.

Retinal injury following blast exposure is closely associated with NLRP3-Caspase-1-GSDMD signaling axis-mediated photoreceptor pyroptosis. Early administration of MCC950 to inhibit this pyroptosis pathway can effectively alleviate neuroinflammation and gliosis, thereby exerting protective effects on the structure and function of retinal photoreceptor cells.