title: Impact of human monocyte and macrophage polarization on NLR expression and NLRP3 inflammasome activation.
abstract: Inflammasomes are multiprotein complexes nucleating around an NLR (Nucleotide-binding domain and Leucine-rich Repeat containing protein), which regulate the secretion of the pro-inflammatory interleukin (IL)-1β and IL-18 cytokines. Monocytes and macrophages, the main cells expressing the inflammasome genes, adapt to their surrounding microenvironment by a phenotypic polarization towards a pro-inflammatory M1 phenotype that promotes inflammation or an anti-inflammatory M2 phenotype important for resolution of inflammation. Despite the importance of inflammasomes in health and disease, little is known about inflammasome gene expression in relevant human cells and the impact of monocyte and macrophage polarization in inflammasome gene expression. We examined the expression of several members of the NLR, caspase and cytokine family, and we studied the activation of the well-described NLRP3 inflammasome in an experimental model of polarized human primary monocytes and monocyte-derived macrophages (M1/M2 phenotypes) before and after activation with LPS, a well-characterized microbial pattern used in inflammasome activation studies. Our results show that the differentiation of monocytes to macrophages alters NLR expression. Polarization using IFN-γ (M1 phenotype), induces among the NLRs studied, only the expression of NOD2. One of the key results of our study is that the induction of NLRP3 expression by LPS is inhibited in the presence of IL-4+IL-13 (M2 phenotype) at both mRNA and protein level in monocytes and macrophages. Unlike caspase-3, the expression of inflammasome-related CASP1 (encodes caspase-1) and CASP4 (encodes caspase-4) is up-regulated in M1 but not in M2 cells. Interestingly, the presence of LPS marginally influenced IL18 mRNA expression and secretion, unlike its impact on IL1B. Our data provide the basis for a better understanding of the role of different inflammasomes within a given environment (M1 and M2) in human cells and their impact in the pathophysiology of several important inflammatory disorders.
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, INSERM, UMR_S 933, Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris, France.
authors.forename: Fawaz
authors.initials: F
authors.lastname: Awad
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, INSERM, UMR_S 933, Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris, France.
authors.forename: Eman
authors.initials: E
authors.lastname: Assrawi
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, INSERM, UMR_S 933, Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Jumeau
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, INSERM, UMR_S 933, Assistance Publique Hôpitaux de Paris, Hôpital Tenon, Service de Médecine interne, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Georgin-Lavialle
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, INSERM, UMR_S 933, Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Cobret
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, INSERM, UMR_S 933, Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Duquesnoy
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, INSERM, UMR_S 933, Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris, France.
authors.forename: William
authors.initials: W
authors.lastname: Piterboth
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, INSERM, UMR_S 933, Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Thomas
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, INSERM, UMR_S 933, Assistance Publique Hôpitaux de Paris, Hôpital Tenon, Service de Médecine interne, Paris, France.
authors.forename: Katia
authors.initials: K
authors.lastname: Stankovic-Stojanovic
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, INSERM, UMR_S 933, Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Louvrier
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, INSERM, UMR_S 933, Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris, France.
authors.forename: Irina
authors.initials: I
authors.lastname: Giurgea
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, INSERM, UMR_S 933, Assistance Publique Hôpitaux de Paris, Hôpital Tenon, Service de Médecine interne, Paris, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Grateau
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, INSERM, UMR_S 933, Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Amselem
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, INSERM, UMR_S 933, Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris, France.
authors.forename: Sonia-Athina
authors.identifier: http://orcid.org/0000-0002-1865-6185
authors.initials: SA
authors.lastname: Karabina
mesh_terms: D020169:Caspases / Q000235:genetics / Q000276:immunology; D016764:Cell Polarity; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000276:immunology*; D000070576:NLR Proteins / Q000235:genetics / Q000276:immunology*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; D058847:Inflammasomes; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; C453881:NLRP3 protein, human; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D020169:Caspases