PMID- 34303829
OWN - NLM
STAT- MEDLINE
DCOM- 20210902
LR  - 20210902
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 173
DP  - 2021 Sep
TI  - Chloroquine inhibits pro-inflammatory effects of heme on macrophages and invivo.
PG  - 104-116
LID - S0891-5849(21)00427-5 [pii]
LID - 10.1016/j.freeradbiomed.2021.07.028 [doi]
AB  - BACKGROUND: Chloroquine has been used successfully to treat Malaria, including by 
      chloroquine-resistant Plasmodium sp., indicating that it has effects on disease 
      itself. Since heme has inflammatory effects and contributes to the pathogenesis 
      of hemolytic diseases, we hypothesize that the anti-inflammatory effect of 
      chloroquine is partially due to its inhibitory effect on heme-induced macrophage 
      activation and on inflammatory tissue damage. METHODS: Bone marrow derived 
      macrophages (BMDMs) were incubated with chloroquine before stimulation with heme, 
      in different conditions, to evaluate cytokines secretion, ROS production, mitogen 
      activated protein kinases (MAPK) or spleen tyrosine kinase (Syk) activation, 
      alone or combined with LPS. The effects of chloroquine upon heme inflammation 
      were also evaluated in vivo, through simultaneous i.p. injection of LPS and heme, 
      intratracheal instillation of Poly-IC followed by heme injection, and in a 
      rhabdomyolysis model. RESULTS: Chloroquine inhibited TNF secretion, mitochondrial 
      ROS production, MAPK, and Syk activation induced by heme. Inhibition of TNF 
      production could be mimicked by zinc ionophore quercetin, but not by primaquine, 
      a chloroquine analog with low affinity for heme. IL-6 and IL-1beta secretions 
      induced by heme in the presence of PRRs agonists were inhibited by chloroquine, 
      but not by calcium chelator BAPTA or inhibitor of endosomal acidification 
      concamycin B. Chloroquine also protected mice from heme inflammatory effects in 
      vivo, inhibiting lethal synergism with PRR agonists, lung pathology caused by 
      heme injection after intratracheal instillation of Poly-IC, and delaying death 
      after rhabdomyolisis. CONCLUSION: Our data indicate that chloroquine might be 
      used as a supportive therapy to control heme-induced deleterious inflammation in 
      different hemolytic diseases.
CI  - Copyright (c) 2021. Published by Elsevier Inc.
FAU - Silva, Rafael Cardoso Maciel Costa
AU  - Silva RCMC
AD  - Laboratorio de Inflamacao e Imunidade, Departamento de Imunologia. Instituto de 
      Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, 21941-902, 
      Rio de Janeiro, Brazil; Institut Necker Enfants Malades. INSERM U1151-CNRS 
      UMR8253, Paris, France; Laboratorio Intermediario de Imunoreceptores e 
      Sinalizacao Celular, Instituto de Biofisica Carlos Chagas Filho, Universidade 
      Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil.
FAU - Tan, Luis
AU  - Tan L
AD  - Laboratorio de Inflamacao e Imunidade, Departamento de Imunologia. Instituto de 
      Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, 21941-902, 
      Rio de Janeiro, Brazil.
FAU - Rodrigues, Danielle Aparecida
AU  - Rodrigues DA
AD  - Laboratorio de Inflamacao e Imunidade, Departamento de Imunologia. Instituto de 
      Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, 21941-902, 
      Rio de Janeiro, Brazil.
FAU - Prestes, Elisa Beatriz
AU  - Prestes EB
AD  - Laboratorio de Inflamacao e Imunidade, Departamento de Imunologia. Instituto de 
      Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, 21941-902, 
      Rio de Janeiro, Brazil; Institut Necker Enfants Malades. INSERM U1151-CNRS 
      UMR8253, Paris, France.
FAU - Gomes, Caroline Pereira
AU  - Gomes CP
AD  - Laboratorio de Inflamacao e Imunidade, Departamento de Imunologia. Instituto de 
      Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, 21941-902, 
      Rio de Janeiro, Brazil.
FAU - Gama, Andreza Moreira
AU  - Gama AM
AD  - Laboratorio de Inflamacao e Imunidade, Departamento de Imunologia. Instituto de 
      Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, 21941-902, 
      Rio de Janeiro, Brazil.
FAU - Oliveira, Pedro Lagerblad de
AU  - Oliveira PL
AD  - Laboratorio de Bioquimica de Insetos, Instituto de Bioquimica Medica Leopoldo de 
      Meis, Universidade Federal do Rio de Janeiro, Brazil.
FAU - Paiva, Claudia Neto
AU  - Paiva CN
AD  - Laboratorio de Inflamacao e Imunidade, Departamento de Imunologia. Instituto de 
      Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, 21941-902, 
      Rio de Janeiro, Brazil.
FAU - Manoury, Benedicte
AU  - Manoury B
AD  - Institut Necker Enfants Malades. INSERM U1151-CNRS UMR8253, Paris, France.
FAU - Bozza, Marcelo Torres
AU  - Bozza MT
AD  - Laboratorio de Inflamacao e Imunidade, Departamento de Imunologia. Instituto de 
      Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, 21941-902, 
      Rio de Janeiro, Brazil. Electronic address: mtbozza@micro.ufrj.br.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210722
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Cytokines)
RN  - 0 (Lipopolysaccharides)
RN  - 42VZT0U6YR (Heme)
RN  - 886U3H6UFF (Chloroquine)
SB  - IM
MH  - Animals
MH  - *Chloroquine
MH  - Cytokines
MH  - *Heme
MH  - Lipopolysaccharides/toxicity
MH  - Macrophage Activation
MH  - Macrophages
MH  - Mice
OTO - NOTNLM
OT  - Chloroquine
OT  - Cytokines
OT  - Heme
OT  - Inflammation
OT  - ROS
EDAT- 2021/07/26 06:00
MHDA- 2021/09/03 06:00
CRDT- 2021/07/25 20:31
PHST- 2021/06/18 00:00 [received]
PHST- 2021/07/19 00:00 [revised]
PHST- 2021/07/20 00:00 [accepted]
PHST- 2021/07/26 06:00 [pubmed]
PHST- 2021/09/03 06:00 [medline]
PHST- 2021/07/25 20:31 [entrez]
AID - S0891-5849(21)00427-5 [pii]
AID - 10.1016/j.freeradbiomed.2021.07.028 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2021 Sep;173:104-116. doi: 
      10.1016/j.freeradbiomed.2021.07.028. Epub 2021 Jul 22.