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AOC3 – modelling allergic inflammation

The immunopathogenesis of asthma involves complex cross-talk between airway epithelial cells, dendritic cells (DCs) and other cells of the innate immune system, and T cells. Although leukocyte migration to airways is a prerequisite for the pathogenesis of asthma, the molecular mechanisms controlling the multistep extravasation cascade of different subsets of leukocytes to airways are not fully understood.

It is evident, however, that the adhesion mechanisms in lung are different when compared with most other tissues, since they are only partially dependent of rolling and selectins and mainly take place in capillaries. Amine oxidase, copper containing 3 (AOC3) is one of the nonclassical endothelial adhesion molecules involved in leukocyte recirculation. It harbors enzyme activity that oxidizes primary amines to produce hydrogen peroxide, aldehyde, and ammonia, which in turn can act as signaling molecules and contribute to leukocyte adhesion. Absence of AOC3, or its inhibition with antibodies or enzyme inhibitors, attenuates inflammatory responses in several different models, including granulocyte influx in LPS-mediated and ischemia–reperfusion triggered models of acute lung injury. However, the in vivo role of AOC3 in allergic inflammation in general and its role in lymphocyte traffic to lung remain unknown. Therefore, the scientists used AOC3-deficient mice to address the contribution of AOC3 in a well-established mouse model of asthma and developed a new protocol for dissecting its involvement during adaptive immune responses in the airways.

To assess the role of AOC3 in the immunopathogenesis of asthma wildtype and AOC3-deficient mice were intraperitoneally sensitized and consecutively challenged with ovalbumin (OVA) in the German Mouse Clinic or OVA, Cholera toxin (CT) and house dust mite (HDM) in Turku. Allergic responses were evaluated by measuring the antibody and cellular distribution.

The data from the OVA challenging imply that AOC3 is not needed for plasma cell differentiation or isotype switching during allergic reactions. Leukocyte recruitment to the lungs of allergen-challenged animals was evaluated from bronchoalveolar lavage fluids (BALFs) by flow cytometry. In the younger 8-week-old cohort, total leukocyte recruitment to BALF of AOC3-deficient animals was statistically significantly reduced in comparison with WT mice and a tendency for a reduced eosinophil amount was observed. Taken together the authors suggest that AOC3 plays a small role in leukocyte recruitment into asthmatic lungs in mice but not appear a significant role in the effector phase of allergen-specific immune responses in the airways. However, it has to be kept in mind that the results from mouse analysis cannot be directly generalized to humans since the authors showed that AOC3 is expressed at a markedly higher level in the pulmonary vasculature in humans than in mice.

Endothelial amine oxidase AOC3 transiently contributes to adaptive immune responses in the airways; Dunkel et al., Eur. J. Immunol. 2014. 0: 1–8 DOI: 10.1002/eji.201444563