title: A Key Role for Inhibins in Dendritic Cell Maturation and Function.
abstract: Inhibins are members of the TGFβ superfamily, which regulate many cellular processes including differentiation, proliferation, survival and apoptosis. Although initially described as hormones regulating the hypothalamus-pituitary-gonadal axis, based on their ability to antagonize Activins, our group has recently reported that they play a role in thymocyte differentiation and survival, as well as in thymic stromal cell maturation and nTreg generation. Here, we used Inhibin knock out mice (Inhα-/-) to investigate the role of Inhibins in peripheral dendritic cell maturation and function. We first demonstrated that LPS treated Inhα+/+ bone marrow derived dendritic cells (BMDC) were capable to produce significant levels of Inhibin A. Interestingly, Inhα-/- BMDC showed reduced MHCII and CD86 upregulation and increased PD-L1 expression in response to LPS compared to Inhα+/+, which correlated with reduced ability to induce proliferation of allogeneic T cells. The "semi-mature" phenotype displayed by Inhα-/- mBMDC correlated with increased levels of IL-10 and slightly decreased IL-6 production after LPS stimulation. In addition, Inhα-/- mBMDC showed impaired migration towards CCL19 and CCL21, assessed by in vitro chemotaxis and in vivo competitive homing experiments, despite their normal CCR7 expression. Furthermore, in vivo LPS-induced DC maturation was also diminished in Inhα-/- mice, specially within the LC (CD207+ CD11b+ CD103-) subpopulation. Finally, analysis of delayed type hypersensitivity responses in Inhα-/- mice, showed reduced ear swelling as a result of reduced cellular infiltration in the skin, correlating with impaired homing of CD207+ DCs to the draining lymph nodes. In summary, our data demonstrate for the first time that Inhibins play a key role in peripheral DC maturation and function, regulating the balance between immunity and tolerance.
authors.affiliation: Departamento de Inmunología. Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico city, Mexico.
authors.forename: Roxana
authors.initials: R
authors.lastname: Olguín-Alor
authors.affiliation: Departamento de Inmunología. Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico city, Mexico.
authors.forename: Marisol
authors.initials: M
authors.lastname: de la Fuente-Granada
authors.affiliation: Unidad de Investigación Médica en Inmunoquímica. Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico city, Mexico.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Bonifaz
authors.affiliation: Unidad de Investigación Médica en Inmunoquímica. Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico city, Mexico.
authors.forename: Laura
authors.initials: L
authors.lastname: Antonio-Herrera
authors.affiliation: Departamento de Inmunología. Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico city, Mexico.
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: García-Zepeda
authors.affiliation: Departamento de Inmunología. Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico city, Mexico.
authors.forename: Gloria
authors.initials: G
authors.lastname: Soldevila
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D006968:Hypersensitivity, Delayed; D007265:Inhibins / Q000502:physiology*; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D013601:T-Lymphocytes / Q000166:cytology
chemical_list: D016753:Interleukin-10; D007265:Inhibins