Histone Deacetylase 6 Regulates α-Tubulin to Inhibit the Stimulator of Interferon Genes/NLR Family Pyrin Domain-Containing 3-Mediated Microglial Pyroptosis Induced by Herpes Simplex Virus Type 1 Infection

Microglia constitute the first line of defense that initiates immune responses against herpes simplex virus type 1 (HSV-1) infection. In HSV-1 infection, the regulatory function of the NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome-mediated pyroptosis in microglia, which acts as an intrinsic antiviral immune response, remains unclear. This study investigated the interaction between pyroptosis and HSV-1 infection. Gasdermin D (GSDMD) is cleaved in HSV-1 infection in vitro and in vivo. Gasdermin D knockdown inhibited pyroptosis and lactate dehydrogenase (LDH) release but enhanced HSV-1 infection. Histone deacetylase 6 (HDAC6) knockdown and inhibition of HDAC6 deacetylase activity by tubacin promoted NLRP3 inflammasome activation, LDH, and mature IL-1β release and microglial pyroptosis, weakening HSV-1 infection. Blocking α-tubulin acetylation attenuated the stimulator of interferon genes–NLRP3 interaction, counteracting the increased GSDMD cleavage by HDAC6 inhibitors and resulting in increased susceptibility to HSV-1 infection. Our findings reveal that HDAC6 inactivates NLRP3-mediated microglial pyroptosis to facilitate HSV-1 infection, providing a new potential strategy for effective antiviral immunotherapy.