4.8 Article

Targeting Macrophage Histone H3 Modification as a Leishmania Strategy to Dampen the NF-κB/NLRP3-Mediated Inflammatory Response

Journal

CELL REPORTS
Volume 30, Issue 6, Pages 1870-+

Publisher

CELL PRESS
DOI: 10.1016/j.celrep.2020.01.030

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Funding

  1. Institut Pasteur International Direction to the International Mixed Unit Inflammation and Leishmania Infection''
  2. Chinese Academy of Sciences [153831KYSB20190008]
  3. French National Research Agency [ANR-10-INSB-04-01]
  4. Conseil de la Region Ile-de-France (Domaine d'Interet Majeur DIM1HEALTH)
  5. Fondation Francaise pour la Recherche Medicale (Programme Grands Equipements)

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Aberrant macrophage activation during intracellular infection generates immunopathologies that can cause severe human morbidity. A better understanding of immune subversion strategies and macrophage phenotypic and functional responses is necessary to design host-directed intervention strategies. Here, we uncover a fine-tuned transcriptional response that is induced in primary and lesional macrophages infected by the parasite Leishmania amazonensis and dampens NF-kappa B and NLRP3 inflammasome activation. Subversion is amastigote-specific and characterized by a decreased expression of activating and increased expression of de-activating components of these pro-inflammatory pathways, thus revealing a regulatory dichotomy that abrogates the anti-microbial response. Changes in transcript abundance correlate with histone H3K9/14 hypoacetylation and H3K4 hypo-trimethylation in infected primary and lesional macrophages at promoters of NF-kappa B-related, pro-inflammatory genes. Our results reveal a Leishmania immune subversion strategy targeting host cell epigenetic regulation to establish conditions beneficial for parasite survival and open avenues for host-directed, anti-microbial drug discovery.

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