Histone deacetylase-2 controls IL-1β production through the regulation of NLRP3 expression and activation in tuberculosis infection

This is the authors' abstract. We don't add key points for this paper.

Histone deacetylases (HDACs) are critical immune regulators. However, their roles in interleukin-1β (IL-1β) production remain unclear. By screening 11 zinc-dependent HDACs with chemical inhibitors, we found that HDAC1 inhibitor, 4-(dimethylamino)-N-[6-(hydroxyamino)-6-oxohexyl]-benzamide (DHOB), enhanced IL-1β production by macrophage and dendritic cells upon TLR4 stimulation or Mycobacterium tuberculosis infection through IL-1β maturation via elevated NLRP3 expression, increased cleaved caspase-1, and enhanced ASC oligomerization. DHOB rescued defective IL-1β production by dendritic cells infected with M. tuberculosis with ESAT-6 deletion, a virulence factor shown to activate NLRP3 inflammasome. DHOB increased IL-1β production and NLRP3 expression in a tuberculosis mouse model. Although DHOB inhibited HDAC activities of both HDAC1 and HDAC2 by direct binding, knockdown of HDAC2, but not HDAC1, increased IL-1β production and NLRP3 expression in M. tuberculosis -infected macrophages. These data suggest that HDAC2, but not HDAC1, controls IL-1β production through NLRP3 inflammasome activation, a mechanism with a significance in chronic inflammatory diseases including tuberculosis.