title: ATP-Induced Inflammation Drives Tissue-Resident Th17 Cells in Metabolically Unhealthy Obesity.
abstract: Obesity-induced inflammation is conducted by a metabolic pathway, which eventually causes activation of specialized immune cells and leads to an unresolved inflammatory response within the tissue. For this reason, it is critically important to determine how hypertrophic fat tissue alters T cell balance to drive inflammation. In this study, we identify the purinergic signaling as a novel mechanism driving the adaptive Th17 response in human visceral adipose tissue (VAT) of metabolically unhealthy obese patients. We demonstrate that ATP acting via the P2X7 receptor pathway promotes a Th17 polarizing microenvironment with high levels of IL-1β, IL-6, and IL-17 in VAT explants from lean donors. Moreover, in vitro blockade of the P2X7 receptor abrogates the levels of these cytokines. These findings are consistent with a greater frequency of Th17 cells in tissue from metabolically unhealthy obese donors, revealed not only by the presence of a baseline Th17-promoting milieu, but also by the higher expression of steadily recognized Th17 markers, such as RORC, IL-17 cytokine, and IL-23R, in comparison with metabolically healthy obese and lean donors. In addition, we demonstrate that CD39 expression on CD4(+)effector T cells represents a novel Th17 marker in the inflamed VAT, which also confers protection against ATP-induced cell death. The manipulation of the purinergic signaling might represent a new therapeutic target to shift the CD4(+)T cell balance under inflammatory conditions.
authors.affiliation: Instituto de Inmunología, Genética y Metabolismo, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, C1120AAF Buenos Aires, Argentina; and.
authors.forename: Julieta B
authors.initials: JB
authors.lastname: Pandolfi
authors.affiliation: División Cirugía Gastroenterológica, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, C1120AAF Buenos Aires, Argentina.
authors.forename: Ariel A
authors.initials: AA
authors.lastname: Ferraro
authors.affiliation: Instituto de Inmunología, Genética y Metabolismo, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, C1120AAF Buenos Aires, Argentina; and.
authors.forename: Inés
authors.initials: I
authors.lastname: Sananez
authors.affiliation: División Cirugía Gastroenterológica, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, C1120AAF Buenos Aires, Argentina.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Gancedo
authors.affiliation: Instituto de Inmunología, Genética y Metabolismo, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, C1120AAF Buenos Aires, Argentina; and.
authors.forename: Plácida
authors.initials: P
authors.lastname: Baz
authors.affiliation: Instituto de Inmunología, Genética y Metabolismo, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, C1120AAF Buenos Aires, Argentina; and.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Billordo
authors.affiliation: Instituto de Inmunología, Genética y Metabolismo, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, C1120AAF Buenos Aires, Argentina; and.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Fainboim
authors.affiliation: Instituto de Inmunología, Genética y Metabolismo, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, C1120AAF Buenos Aires, Argentina; and arruvitol@gmail.com.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Arruvito
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000328:Adult; D015703:Antigens, CD / Q000096:biosynthesis; D017209:Apoptosis / Q000502:physiology; D001081:Apyrase / Q000096:biosynthesis; D060833:Cellular Microenvironment / Q000276:immunology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D008297:Male; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D009765:Obesity / Q000276:immunology* / Q000473:pathology; D018123:Receptors, Interleukin / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C508717:IL17A protein, human; C508585:IL1B protein, human; C515500:IL23R protein, human; C508600:IL6 protein, human; D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C546468:P2RX7 protein, human; C539900:RORC protein, human; D018123:Receptors, Interleukin; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D001081:Apyrase; C067869:CD39 antigen