Small-molecule screening identifies Syk kinase inhibition and rutaecarpine as modulators of macrophage training and SARS-CoV-2 infection.
CP: Immunology
LPS tolerance
NFAT-2
SARS-CoV-2
Syk inhibition
innate immune training
rutaecarpine
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
04 10 2022
04 10 2022
Historique:
received:
01
05
2022
revised:
01
07
2022
accepted:
12
09
2022
pubmed:
1
10
2022
medline:
12
10
2022
entrez:
30
9
2022
Statut:
ppublish
Résumé
Biologically active small molecules can impart modulatory effects, in some cases providing extended long-term memory. In a screen of biologically active small molecules for regulators of tumor necrosis factor (TNF) induction, we identify several compounds with the ability to induce training effects on human macrophages. Rutaecarpine shows acute and long-term modulation, enhancing lipopolysaccharide (LPS)-induced pro-inflammatory cytokine secretion and relieving LPS tolerance in human macrophages. Rutaecarpine inhibits β-glucan-induced H3K4Me3 marks at the promoters of several pro-inflammatory cytokines, highlighting the potential of this molecule to modulate chromosomal topology. Syk kinase inhibitor (SYKi IV), another screen hit, promotes an enhanced response to LPS similar to that previously reported for β-glucan-induced training. Macrophages trained with SYKi IV show a high degree of resistance to influenza A, multiple variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and OC43 coronavirus infection, highlighting a potential application of this molecule and other SYKis as prophylactic treatments for viral susceptibility.
Identifiants
pubmed: 36179680
pii: S2211-1247(22)01282-7
doi: 10.1016/j.celrep.2022.111441
pmc: PMC9474420
pii:
doi:
Substances chimiques
Cytokines
0
Indole Alkaloids
0
Lipopolysaccharides
0
Quinazolinones
0
Tumor Necrosis Factor-alpha
0
beta-Glucans
0
rutecarpine
8XZV289PRY
SYK protein, human
EC 2.7.10.2
Syk Kinase
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
111441Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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