title: Nrf2-driven CD36 and HO-1 gene expression in circulating monocytes correlates with favourable clinical outcome in pregnancy-associated malaria.
abstract: BACKGROUND
  Pregnancy-associated malaria (PAM) constitutes one of the most severe forms of malaria infection leading to fetal growth restriction and high risk of infant death. The severity of the pathology is largely attributed to the recruitment of monocytes and macrophages in the placenta which is evidenced by dysregulated inflammation found in placental blood. Importantly, CD36(+) monocytes/macrophages are also thought to participate in the tight control of the pro- and anti-inflammatory responses following Plasmodium detection through elimination of apoptotic cells and malaria-infected erythrocytes, internalization and recycling of oxidized forms of low-density lipoprotein and collaboration with TLR2 in pro-inflammatory response. Interestingly, previous work demonstrated that CD36 expression was upregulated on inflammatory macrophages following stimulation of the Nrf2 transcription factor, whilst the PPARγ pathway was inhibited and non-functional in the same inflammatory conditions. This current study examined the possible role of Nrf2-driven gene expression, CD36 and Haem-Oxygenase-1 (HO-1), in PAM clinical outcomes.
  
  
  METHODS
  Clinical data and biological samples including peripheral blood mononuclear cells were collected from 27 women presenting PAM. Polychromatic flow cytometry was used to characterize innate immune cell subpopulations and quantify CD36 protein expression level on monocytes. mRNA levels of CD36, PPARγ, Nrf2 and HO-1 were determined by qPCR and related to clinical outcomes. Finally, the capacity of monocytes to modulate CD36 expression upon rosiglitazone or sulforaphane treatment, two respective PPARγ or Nrf2 activators, was also investigated.
  
  
  RESULTS
  The CD36 receptor, mostly expressed by CD14(+) circulating monocytes, statistically correlated with increased infant birth weights. Interestingly, mRNA levels of the transcription factor Nrf2 and the enzyme HO-1 also correlated with lower parasitaemia and increased infant birth weight, while PPARγ mRNA levels did not. Finally, monocytes isolated from low infant birth weight pregnant women were capable of up-regulating CD36 via the Nrf2 pathway ex vivo.
  
  
  CONCLUSIONS
  Altogether these results suggest that Nrf2-driven CD36 and HO-1 expression on innate immune cells could contribute to a protective and detoxifying mechanism during PAM. More powered and mechanistical studies are however needed to strengthen the conclusions of this study.
authors.affiliation: Institut de Recherche pour le Développement (IRD), Université Paul Sabatier Toulouse III, UMR 152 Pharma-Dev, CHU Rangueil, Bâtiment L1, 1 Avenue du Pr Jean Poulhès, 31059, Toulouse, France. agnes.aubouy@ird.fr.
authors.forename: Agnès
authors.initials: A
authors.lastname: Aubouy
authors.affiliation: Institut de Recherche pour le Développement (IRD), Université Paul Sabatier Toulouse III, UMR 152 Pharma-Dev, CHU Rangueil, Bâtiment L1, 1 Avenue du Pr Jean Poulhès, 31059, Toulouse, France. david.olagnier@mail.mcgill.ca.|Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Canada. david.olagnier@mail.mcgill.ca.
authors.forename: David
authors.initials: D
authors.lastname: Olagnier
authors.affiliation: Institut de Recherche pour le Développement (IRD), PRES Sorbonne Paris Cité, Université Paris Descartes, UMR 216 Mère et enfant face aux infections tropicales, Paris, France. gwladys.bertin@ird.fr.
authors.forename: Gwladys
authors.initials: G
authors.lastname: Bertin
authors.affiliation: Centre d'Etude et de Recherche sur le Paludisme Associé à la Grossesse et l'Enfance (CERPAGE), Cotonou, Benin. ezinmegnon.sem@gmail.com.
authors.forename: Sem
authors.initials: S
authors.lastname: Ezinmegnon
authors.affiliation: Institut de Recherche pour le Développement (IRD), Université Paul Sabatier Toulouse III, UMR 152 Pharma-Dev, CHU Rangueil, Bâtiment L1, 1 Avenue du Pr Jean Poulhès, 31059, Toulouse, France. clarisse.majorel@ird.fr.|Laboratoire Insulaire du Vivant et de l'Environnement (LIVE-EA 4243), Université de la Nouvelle-Caledonie (UNC), Nouméa, New Caledonia. clarisse.majorel@ird.fr.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Majorel
authors.affiliation: Institut de Recherche pour le Développement (IRD), Université Paul Sabatier Toulouse III, UMR 152 Pharma-Dev, CHU Rangueil, Bâtiment L1, 1 Avenue du Pr Jean Poulhès, 31059, Toulouse, France. mimar.saliha1@free.fr.
authors.forename: Saliha
authors.initials: S
authors.lastname: Mimar
authors.affiliation: Centre d'Etude et de Recherche sur le Paludisme Associé à la Grossesse et l'Enfance (CERPAGE), Cotonou, Benin. massougbodjiachille@yahoo.fr.
authors.forename: Achille
authors.initials: A
authors.lastname: Massougbodji
authors.affiliation: Institut de Recherche pour le Développement (IRD), PRES Sorbonne Paris Cité, Université Paris Descartes, UMR 216 Mère et enfant face aux infections tropicales, Paris, France. philippe.deloron@ird.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Deloron
authors.affiliation: Institut de Recherche pour le Développement (IRD), Université Paul Sabatier Toulouse III, UMR 152 Pharma-Dev, CHU Rangueil, Bâtiment L1, 1 Avenue du Pr Jean Poulhès, 31059, Toulouse, France. bernard.pipy@inserm.fr.
authors.forename: Bernard
authors.initials: B
authors.lastname: Pipy
authors.affiliation: Institut de Recherche pour le Développement (IRD), Université Paul Sabatier Toulouse III, UMR 152 Pharma-Dev, CHU Rangueil, Bâtiment L1, 1 Avenue du Pr Jean Poulhès, 31059, Toulouse, France. agnes.coste@univ-tlse3.fr.
authors.forename: Agnès
authors.initials: A
authors.lastname: Coste
mesh_terms: D000293:Adolescent; D000328:Adult; D001541:Benin / Q000453:epidemiology; D001724:Birth Weight; D018955:CD36 Antigens / Q000235:genetics* / Q000378:metabolism; D005260:Female; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D016778:Malaria, Falciparum / Q000453:epidemiology* / Q000469:parasitology; D009000:Monocytes / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D018512:Parasitemia / Q000453:epidemiology* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000502:physiology*; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000453:epidemiology* / Q000469:parasitology; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D018955:CD36 Antigens; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D047495:PPAR gamma; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1