β-arrestin 2 inhibits proinflammatory chemokine production and attenuates contact allergic inflammation in the skin.

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.