Acute Hemolysis and Heme Suppress Anti-CD40 Antibody-Induced Necro-Inflammatory Liver Disease.
Albumins
/ metabolism
Animals
Antibodies
/ adverse effects
Biopsy
CD40 Antigens
/ antagonists & inhibitors
Disease Models, Animal
Disease Susceptibility
Erythrocytes
/ drug effects
Gene Expression Profiling
Heme
/ metabolism
Hemolysis
/ immunology
Hepatitis
/ etiology
Iron
/ metabolism
Macrophages
/ immunology
Mice
Mice, Knockout
Phenylhydrazines
/ adverse effects
Porphyrins
/ metabolism
Protein Binding
anti-CD40
erythrophagocytosis
heme
hepatitis
inflammation
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2021
2021
Historique:
received:
15
03
2021
accepted:
22
04
2021
entrez:
31
5
2021
pubmed:
1
6
2021
medline:
27
10
2021
Statut:
epublish
Résumé
Clearance of red blood cells and hemoproteins is a key metabolic function of macrophages during hemolytic disorders and following tissue injury. Through this archetypical phagocytic function, heme is detoxified and iron is recycled to support erythropoiesis. Reciprocal interaction of heme metabolism and inflammatory macrophage functions may modify disease outcomes in a broad range of clinical conditions. We hypothesized that acute hemolysis and heme induce acute anti-inflammatory signals in liver macrophages. Using a macrophage-driven model of sterile liver inflammation, we showed that phenylhydrazine (PHZ)-mediated acute erythrophagocytosis blocked the anti-CD40 antibody-induced pathway of macrophage activation. This process attenuated the inflammatory cytokine release syndrome and necrotizing hepatitis induced by anti-CD40 antibody treatment of mice. We further established that administration of heme-albumin complexes specifically delivered heme to liver macrophages and replicated the anti-inflammatory effect of hemolysis. The anti-inflammatory heme-signal was induced in macrophages by an increased intracellular concentration of the porphyrin independently of iron. Overall, our work suggests that induction of heme-signaling strongly suppresses inflammatory macrophage function, providing protection against sterile liver inflammation.
Identifiants
pubmed: 34054870
doi: 10.3389/fimmu.2021.680855
pmc: PMC8149790
doi:
Substances chimiques
Albumins
0
Antibodies
0
CD40 Antigens
0
Phenylhydrazines
0
Porphyrins
0
phenylhydrazine
064F424C9K
Heme
42VZT0U6YR
Iron
E1UOL152H7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
680855Informations de copyright
Copyright © 2021 Pfefferlé, Ingoglia, Schaer, Hansen, Schulthess, Humar, Schaer and Vallelian.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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