title: β-arrestin 2 inhibits proinflammatory chemokine production and attenuates contact allergic inflammation in the skin.
abstract: β-Arrestins participate in G-protein receptor signaling and act as adapter proteins that direct the recruitment, activation, and scaffolding of various cytoplasmic signaling complexes. β-Arrestin 2-deficient (Arrb2(-/-)) mice show decreased T-cell recruitment into allergic lung tissue but increased neutrophil infiltration into wounded skin. Given these opposing effects in different immune cell subsets, we investigated the role of β-arrestin 2 in the regulation of contact hypersensitivity responses. We observed significantly increased allergic ear swelling to the obligate contact sensitizers DNFB and FITC in Arrb2(-/-) compared with wild-type mice. Immunohistological analyses revealed strikingly increased neutrophil infiltration with abundant subcorneal pustules in inflamed ear tissue of DNFB-allergic Arrb2(-/-) mice. Experiments involving adoptive transfers of sensitized lymphocytes and bone marrow chimeric mice indicated that β-arrestin 2 exerts its anti-inflammatory effects predominantly through radioresistant, skin-resident cells in the challenge phase of contact hypersensitivity. As a potential mechanism, we found that primary cultures of β-arrestin 2-deficient keratinocytes secreted higher levels of neutrophil-attracting chemokines including CXCL1/KC in response to T cell-derived cytokines in vitro. These experimental results support a model in which β-arrestin 2 inhibits the production of proinflammatory chemokines, which limits the recruitment of myeloid immune cells and thereby attenuates allergic skin inflammation.
authors.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, Bonn, Germany. Electronic address: evelyn.gaffal@ukb.uni-bonn.de.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Gaffal
authors.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, Bonn, Germany.
authors.forename: Mira
authors.initials: M
authors.lastname: Jakobs
authors.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, Bonn, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Glodde
authors.affiliation: Institute for Pharmaceutical Biology, University of Bonn, Bonn, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Schröder
authors.affiliation: Institute for Pharmaceutical Biology, University of Bonn, Bonn, Germany.
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
authors.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, Bonn, Germany. Electronic address: thomas.tueting@ukb.uni-bonn.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
mesh_terms: D000818:Animals; D019390:Arrestins / Q000502:physiology*; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis*; D017449:Dermatitis, Allergic Contact / Q000276:immunology* / Q000517:prevention & control; D004139:Dinitrofluorobenzene; D015603:Keratinocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology; D011836:Radiation Tolerance; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605258:Arrb2 protein, mouse; D019390:Arrestins; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D004139:Dinitrofluorobenzene