|Siracusa, Mark - JOHNS HOPKINS U, BALT MD|
|Scott, Alan - JOHNS HOPKINS U, BALT MD|
Submitted to: Journal of Leukocyte Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 21, 2008
Publication Date: December 1, 2008
Citation: Siracusa, M.C., Reece, J.J., Urban Jr, J.F., Scott, A.L. 2008. Dynamics of lung macrophage activation in response to helminth infection. Journal of Leukocyte Biology. 84(6):1422-1423. Interpretive Summary: There is growing concern over the rise in allergic disease in westernized societies that is not observed in areas of the world where parasitic infections are still prevalent. This interesting and seemingly contradictory relationship may exist because of changes in local cell populations at mucosal surfaces of the body such as the lung. In the present study, the level of inflammation in the lungs, and cellular and molecular markers of a population of cells called alternatively activated macrophages (AAMs), were evaluated after exposure of mice to a parasitic worm that migrates through the lungs. The response that is induced in many ways mimics responses to allergens that are inhaled and initiate symptoms of allergic disease. It was observed that the AAMs change over time after infection to first express a pro-inflammatory role to presumably engage the local infection, but then change to an anti-inflammatory role to control the tissue destruction and repair mechanisms needed to bring the tissues back to normal function. These results indicate that molecules that simulate the activity of worm infection without the harmful passage of the infection through the lungs may provide useful tools to regulate the inflammation that often is associated with an allergic response and more rapidly reverse the consequences of local inflammation. Some of these molecules can be modulated by dietary influences, such as the appropriate presence of vitamin A that contributes to the function of AAMs in the lungs. These results are important as a model of human allergic disease, and provide researchers with a target to alter dysfunctional immune responses with products that mimic exposure to worms, including those introduced into the diet.
Technical Abstract: Most of our understanding of the development and phenotype of alternatively activated macrophages (AAM) has been obtained from studies investigating the response of bone marrow- and peritoneal-derived cells to IL-4 or IL-13 stimulation. Comparatively little is known about the development of the AAMs in the lungs and how the complex signals associated with pulmonary inflammation influence the AAM phenotype. Here we use a Nippostrongylus brasiliensis infection to define the development, surface phenotype, expression profile, and function of AAMs in the lungs. AAMs develop rapidly and undergo distinct phases of activation that result in significant changes in cell morphology, surface marker expression, and cytokine production. During the first few days of infection alveolar macrophages take on a foamy phenotype, up-regulate MHC and co-stimulatory molecules, and produce cytokines, which suggests a proinflammatory role. Between days 4 and 8 post-infection AAMs adopt a dense granular phenotype. In addition, the AAMs isolated from the lungs between days 8 and 15 post-infection show reduced levels of co-stimulatory molecules, elevated levels of PDL1 and PDL2, and an increase in IL-10 production, suggesting that these cells are now anti-inflammatory in nature. Functionally, AAMs isolated on 13-15 days post-infection demonstrate an enhanced capacity to take up and sequester antigen but were poor antigen-presenting cells and inhibited CD4 T cell activation. The present observations suggest that alternative activation is a phase-specific process that is significantly influenced by factors in the pulmonary environment such as oxidized lipids, surfactant proteins, and apoptotic bodies.