The scaffolding protein AKAP79/150 shapes innate immune responses to allergen

Abstract

Abstract Inhalation of house dust mite-derived allergens is a major factor leading to the development of asthma both in children and adults. Allergens stimulate Ca2+-dependent pro-inflammatory cytokine and chemokine gene expression through the opening of ORAI1 Ca2+ channels in the surface membrane of various immune cell-types within the lung. ORAI1 participates in a signalosome with the scaffolding protein A-kinase anchoring protein (AKAP)79/150 (encoded by the Akap5 gene), which binds numerous protein kinases, calcineurin and transcription factors required for cytokine expression. However, the role of AKAP79/150 in immune cell activation and the development of airway inflammation in response to allergens has not been established. We found that AKAP79/150 is expressed in mast cells and macrophages, where it has a pivotal role in driving pro-inflammatory cytokine production in response to house dust mite challenge. By contrast, AKAP79/150 expression in T cells was low and had little impact on cytokine release following T cell activation. Akap5−/− mice exhibited significantly reduced type 2 inflammation in the lungs following HDM exposure compared with wild-type controls. Our data demonstrate that AKAP79/150 is an important co-ordinator of inflammation within the lung in response to airborne allergens, through actions primarily on cells of the innate immune system.