Neutral sphingomyelinase 2 regulates inflammatory responses in monocytes/macrophages induced by TNF-α.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
08 10 2020
08 10 2020
Historique:
received:
13
05
2020
accepted:
17
09
2020
entrez:
9
10
2020
pubmed:
10
10
2020
medline:
5
1
2021
Statut:
epublish
Résumé
Obesity is associated with elevated levels of TNF-α and proinflammatory CD11c monocytes/macrophages. TNF-α mediated dysregulation in the plasticity of monocytes/macrophages is concomitant with pathogenesis of several inflammatory diseases, including metabolic syndrome, but the underlying mechanisms are incompletely understood. Since neutral sphingomyelinase-2 (nSMase2: SMPD3) is a key enzyme for ceramide production involved in inflammation, we investigated whether nSMase2 contributed to the inflammatory changes in the monocytes/macrophages induced by TNF-α. In this study, we demonstrate that the disruption of nSMase activity in monocytes/macrophages either by chemical inhibitor GW4869 or small interfering RNA (siRNA) against SMPD3 results in defects in the TNF-α mediated expression of CD11c. Furthermore, blockage of nSMase in monocytes/macrophages inhibited the secretion of inflammatory mediators IL-1β and MCP-1. In contrast, inhibition of acid SMase (aSMase) activity did not attenuate CD11c expression or secretion of IL-1β and MCP-1. TNF-α-induced phosphorylation of JNK, p38 and NF-κB was also attenuated by the inhibition of nSMase2. Moreover, NF-kB/AP-1 activity was blocked by the inhibition of nSMase2. SMPD3 was elevated in PBMCs from obese individuals and positively corelated with TNF-α gene expression. These findings indicate that nSMase2 acts, at least in part, as a master switch in the TNF-α mediated inflammatory responses in monocytes/macrophages.
Identifiants
pubmed: 33033337
doi: 10.1038/s41598-020-73912-5
pii: 10.1038/s41598-020-73912-5
pmc: PMC7544688
doi:
Substances chimiques
Tumor Necrosis Factor-alpha
0
SMPD3 protein, human
EC 3.1.4.12
Sphingomyelin Phosphodiesterase
EC 3.1.4.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
16802Subventions
Organisme : NCI NIH HHS
ID : P01 CA097132
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM118128
Pays : United States
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