title: Involvement of Nod2 in the innate immune response elicited by malarial pigment hemozoin.
abstract: In malaria, the evidence concerning the nucleotide-binding, oligomerization domain (NOD) 2 (NOD2) receptor is fragmented and the stimuli that might activate NOD2 are not well characterized. We investigated the role of NOD2 in vitro in the response of macrophages to Plasmodium falciparum products. Immortalized or primary bone marrow derived macrophages from wild type C57Bl/6 mice, or knockout mice for NOD2 or its adaptor proteins, were either primed with interferon gamma or left untreated, and stimulated with parasite products. Both lysates of infected erythrocytes or hemozoin induced higher levels of nitric oxide in primed than in unprimed wild type macrophages. When stimulated with hemozoin, primed macrophages knockout for NOD2, or for its adaptor proteins, produced significantly lower nitric oxide levels compared to wild type cells. Differently from hemozoin, the use of β-hematin (synthetic hemozoin) as stimulus showed that NOD2 is dispensable. Furthermore, the production of inflammatory cytokines by wild type cells treated with hemozoin was not dependent on NOD2. These data indicate that parasite components present in the hemozoin, differently from β-hematin, induce the production of nitric oxide through the activation of NOD2, whereas the production of inflammatory cytokines, like TNF-α or MIP-2 (CXCL2), seems to be NOD2 independent.
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano MI 20133, Italy.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Corbett
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano MI 20133, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Parapini
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano MI 20133, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: D'Alessandro
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano MI 20133, Italy.
authors.forename: Diletta
authors.initials: D
authors.lastname: Scaccabarozzi
authors.affiliation: University of Massachusetts Medical School, Division of Infectious Diseases, Massachusetts, MA 01605, USA; Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil.
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Rocha
authors.affiliation: Department of Chemistry, University of Cape Town, Private Bag X3, Rondebosch 7701, South Africa.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Egan
authors.affiliation: Department of Chemistry, University of Cape Town, Private Bag X3, Rondebosch 7701, South Africa.
authors.forename: Aneesa
authors.initials: A
authors.lastname: Omar
authors.affiliation: AVIS Comunale di Milano, Milano MI 20133, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Galastri
authors.affiliation: University of Massachusetts Medical School, Division of Infectious Diseases, Massachusetts, MA 01605, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: University of Massachusetts Medical School, Division of Infectious Diseases, Massachusetts, MA 01605, USA.
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano MI 20133, Italy. Electronic address: donatella.taramelli@unimi.it.
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.affiliation: Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli Studi di Milano, Milano MI 20133, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Basilico
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D006420:Hemeproteins / Q000276:immunology*; D006801:Humans; D008288:Malaria / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000276:immunology; D053473:Nod2 Signaling Adaptor Protein / Q000276:immunology*
chemical_list: D016207:Cytokines; D006420:Hemeproteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; C020753:hemozoin
keywords: Cytokines; NOD2; Natural hemozoin; Nitric oxide; Plasmodium falciparum; Synthetic hemozoin (β-hematin)