A role for fatty acid binding proteins in airway immune responses

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Copyright: Schilter, Heidi Campos
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Abstract
The airway epithelium plays a critical role in the pathogenesis of asthma. It forms the primary defense against inhaled exogenous substances and is also a source of diverse inflammatory mediators such as cytokines, chemokines, cell adhesion molecules and other products that regulate airway physiology. Epithelial cells also aid in the clearance of tissue leukocytes, by serving as a gateway for transepithelial migration of leukocytes into the lung lumen. The central role of epithelium in controlling leukocyte recruitment and egress, led to the identification of molecules regulated in bronchial epithelium during inflammatory responses. One of the molecules highly regulated in airway epithelial cells by the Th2 cytokines IL-4 and IL-13 was the metabolism related lipid chaperone, fatty acid binding protein 5 (FABP5, also named mal1). mal1 plays a role in metabolic homeostasis, and lack of FABP5 moderately protects mice from atherosclerosis and insulin resistance. Of all of the FABPs, mal1 shows the most striking association with epithelial cell expression, although the functional relevance of this is unclear. With the use of immunised mal1-deficient mice, hybridomas that secreted specific mal1 antibodies were successfully generated. These antibodies were crucial in determining mal1 function during asthma pathogenesis. Using mal1-deficient mice in an allergic airway inflammation model, leukocyte clearance via egress to the lung lumen was almost completely dependent on mal1 function. In addition, leukocyte clearance was enhanced by treatment of wild-type mice with C16:1n7-palmitoleate, a mal1-regulated lipokine that affects metabolic homeostasis. mal1 affected the expression of one of the main epithelial cell adhesion molecules, E-Cadherin, which is necessary for tight junction formation and a main regulator of leukocyte transepithelial migration. Transepithelial migration of leukocytes in vitro was impeded by mal1 deficiency, in an E-Cadherin and PPAR-γ dependent manner. In addition to the immune functions of mal1 another FABP, aP2, was also found to regulate immune responses. aP2 mediated type 1 antibody and cytokine production which enhanced the protection of aP2-deficient mice against viral infection. However, the up-regulation of these responses exacerbated inflammation during K/BxN arthritis. These results provide a cellular and molecular role for mal1 in epithelial cell function, and suggest a new avenue to explore connections between metabolism and inflammatory disease.
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Author(s)
Schilter, Heidi Campos
Supervisor(s)
Mackay, Charles
Sewell, William
Hansbro, Philip
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Publication Year
2010
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
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