Dichotomous Role of Plasmin in Regulation of Macrophage Function after Acetaminophen Overdose.
Journal
The American journal of pathology
ISSN: 1525-2191
Titre abrégé: Am J Pathol
Pays: United States
ID NLM: 0370502
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
13
03
2019
revised:
25
06
2019
accepted:
01
07
2019
pubmed:
6
8
2019
medline:
28
3
2020
entrez:
6
8
2019
Statut:
ppublish
Résumé
Kupffer cells and monocyte-derived macrophages are critical for liver repair after acetaminophen (APAP) overdose. These cells produce promitogenic cytokines and growth factors, and they phagocytose dead cell debris, a process that is critical for resolution of inflammation. The factors that regulate these dynamic functions of macrophages after APAP overdose, however, are not fully understood. We tested the hypothesis that the fibrinolytic enzyme, plasmin, is a key regulator of macrophage function after APAP-induced liver injury. In these studies, inhibition of plasmin in mice with tranexamic acid delayed up-regulation of proinflammatory cytokines after APAP overdose. In culture, plasmin directly, and in synergy with high-mobility group B1, stimulated Kupffer cells and bone marrow-derived macrophages to produce cytokines by a mechanism that required NF-κB. Inhibition of plasmin in vivo also prevented trafficking of monocyte-derived macrophages into necrotic lesions after APAP overdose. This prevented phagocytic removal of dead cells, prevented maturation of monocyte-derived macrophages into F4/80-expressing macrophages, and prevented termination of proinflammatory cytokine production. Our studies reveal further that phagocytosis is an important stimulus for cessation of proinflammatory cytokine production as treatment of proinflammatory, monocyte-derived macrophages, isolated from APAP-treated mice, with necrotic hepatocytes decreased expression of proinflammatory cytokines. Collectively, these studies demonstrate that plasmin is an important regulator of macrophage function after APAP overdose.
Identifiants
pubmed: 31381887
pii: S0002-9440(19)30657-1
doi: 10.1016/j.ajpath.2019.07.003
pmc: PMC6892227
pii:
doi:
Substances chimiques
Analgesics, Non-Narcotic
0
Inflammation Mediators
0
Acetaminophen
362O9ITL9D
Fibrinolysin
EC 3.4.21.7
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1986-2001Subventions
Organisme : NIEHS NIH HHS
ID : T32 ES007255
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK120531
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES024966
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK105099
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK073566
Pays : United States
Informations de copyright
Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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