Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development.
TREM2
chronic inflammation
efferocytosis
nonalcoholic steatohepatitis
proinflammatory cytokines
Journal
Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918
Informations de publication
Date de publication:
10 01 2023
10 01 2023
Historique:
received:
26
04
2022
revised:
12
08
2022
accepted:
22
11
2022
pmc-release:
10
01
2024
pubmed:
16
12
2022
medline:
14
1
2023
entrez:
15
12
2022
Statut:
ppublish
Résumé
Obesity-induced chronic liver inflammation is a hallmark of nonalcoholic steatohepatitis (NASH)-an aggressive form of nonalcoholic fatty liver disease. However, it remains unclear how such a low-grade, yet persistent, inflammation is sustained in the liver. Here, we show that the macrophage phagocytic receptor TREM2, induced by hepatocyte-derived sphingosine-1-phosphate, was required for efferocytosis of lipid-laden apoptotic hepatocytes and thereby maintained liver immune homeostasis. However, prolonged hypernutrition led to the production of proinflammatory cytokines TNF and IL-1β in the liver to induce TREM2 shedding through ADAM17-dependent proteolytic cleavage. Loss of TREM2 resulted in aberrant accumulation of dying hepatocytes, thereby further augmenting proinflammatory cytokine production. This ultimately precipitated a vicious cycle that licensed chronic inflammation to drive simple steatosis transition to NASH. Therefore, impaired macrophage efferocytosis is a previously unrecognized key pathogenic event that enables chronic liver inflammation in obesity. Blocking TREM2 cleavage to restore efferocytosis may represent an effective strategy to treat NASH.
Identifiants
pubmed: 36521495
pii: S1074-7613(22)00603-3
doi: 10.1016/j.immuni.2022.11.013
pmc: PMC9839616
mid: NIHMS1855052
pii:
doi:
Substances chimiques
TREM2 protein, human
0
Membrane Glycoproteins
0
Receptors, Immunologic
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
58-77.e11Subventions
Organisme : NCI NIH HHS
ID : R01 CA233794
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA255621
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK099558
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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