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

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), enh...

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Autores principales: Moreira, Jôsimar Dornelas, Iakhiaev, Alexei, Vankayalapati, Ramakrishna, Jung, Bock-Gie, Samten, Buka
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9379586/
https://www.ncbi.nlm.nih.gov/pubmed/35982796
http://dx.doi.org/10.1016/j.isci.2022.104799
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author Moreira, Jôsimar Dornelas
Iakhiaev, Alexei
Vankayalapati, Ramakrishna
Jung, Bock-Gie
Samten, Buka
author_facet Moreira, Jôsimar Dornelas
Iakhiaev, Alexei
Vankayalapati, Ramakrishna
Jung, Bock-Gie
Samten, Buka
author_sort Moreira, Jôsimar Dornelas
collection PubMed
description 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.
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spelling pubmed-93795862022-08-17 Histone deacetylase-2 controls IL-1β production through the regulation of NLRP3 expression and activation in tuberculosis infection Moreira, Jôsimar Dornelas Iakhiaev, Alexei Vankayalapati, Ramakrishna Jung, Bock-Gie Samten, Buka iScience Article 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. Elsevier 2022-07-20 /pmc/articles/PMC9379586/ /pubmed/35982796 http://dx.doi.org/10.1016/j.isci.2022.104799 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Moreira, Jôsimar Dornelas
Iakhiaev, Alexei
Vankayalapati, Ramakrishna
Jung, Bock-Gie
Samten, Buka
Histone deacetylase-2 controls IL-1β production through the regulation of NLRP3 expression and activation in tuberculosis infection
title Histone deacetylase-2 controls IL-1β production through the regulation of NLRP3 expression and activation in tuberculosis infection
title_full Histone deacetylase-2 controls IL-1β production through the regulation of NLRP3 expression and activation in tuberculosis infection
title_fullStr Histone deacetylase-2 controls IL-1β production through the regulation of NLRP3 expression and activation in tuberculosis infection
title_full_unstemmed Histone deacetylase-2 controls IL-1β production through the regulation of NLRP3 expression and activation in tuberculosis infection
title_short Histone deacetylase-2 controls IL-1β production through the regulation of NLRP3 expression and activation in tuberculosis infection
title_sort histone deacetylase-2 controls il-1β production through the regulation of nlrp3 expression and activation in tuberculosis infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9379586/
https://www.ncbi.nlm.nih.gov/pubmed/35982796
http://dx.doi.org/10.1016/j.isci.2022.104799
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