Histone deacetylase-1 controls IL-1β production through the regulation of NLRP3 expression and activation in tuberculosis infection

• Published in: The Journal of immunology (1950) 2021-05, Vol.206 (1_Supplement), p.99-99.11
• Main Authors: Moreira, Jôsimar Dornelas, Vankayalapati, Ramakrishna, Samten, Buka
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.206.Supp.99.11

Although IL-1b is required for the protection against Mycobacterium tuberculosis (Mtb) infection, its uncontrolled production is associated with chronic inflammation and lung damage in Tuberculosis. Epigenetic effector molecules histone deacetylases (HDACs) play critical roles in tumorigenesis and immune regulation, however their roles in IL-1β production remain unexplored. Initial screening of 11 variants of HDAC with their chemical inhibitors identified that inhibition of HDAC-1 promotes secretion of IL-1β and increases the lysine acetylation of histone H3 by primary macrophages and dendritic cells (DCs) in response to LPS/CD40L, IFN-γ stimulation or Mtb infection without affecting pro-IL-1β and IL-6. Inhibition of NLRP3 or Caspase-1 reversed this effect of HDAC-1 inhibition without affecting cell viability, implying the involvement of NLRP3 inflammasome activation. Consistently, HDAC-1 inhibition further elevated the expression of both mRNA and protein of NLRP3 in macrophages and DCs under stimulation and increased levels of cleaved Caspase-1 and mature IL-1β in the culture supernatants. Mtb infection and stimulation with LPS/CD40L of these cells induced increased expression and phosphorylation of HDAC-1 and increased HDAC-1 activity in cell lysates which was suppressed by HDAC-1 inhibitor. Treatment of low dose aerosol Mtb-infected mice with HDAC-1 inhibitor increased IL-1β in mice lungs without affecting IL-6 production. These suggest that HDAC-1 controls IL-1β maturation via regulation of NLRP3 expression and activation, thus suggesting a novel mechanism for the regulation of IL-1β, a major inflammatory cytokine in tuberculosis infection and other inflammatory diseases.