Alternative macrophage activation regulates inflammatory responses to pathogenic organisms. Most work to date has characterized their role in Th2-type immune responses. Alternatively activated macrophages (AAM) have been shown to inhibit classically activated macrophage proliferation and function, as well as to suppress T cell mediated immune responses through the production of the type II cytokine transforming growth factor (TGF)-? and arginase-1. While primarily functioning to orchestrate remodeling and repair mechanisms, arginase-1 and TGF? are also important in controlling lung homeostasis and suppressing inflammation. The function of AAM in regulating the inflammatory response to extracellular Gram-negative bacterial infection in the lungs has not been characterized. Understanding the role of AAM in this setting is critical for advancing our understanding of immune mechanisms affecting patients with cystic fibrosis (CF) and other chronic pulmonary inflammatory conditions. CF causes progressive, life-threatening lung damage due in large part to repeated, dysregulated inflammatory responses to Pseudomonas aeruginosa infection. Therefore, this work will address the hypothesis that alternatively activated macrophages decrease pulmonary inflammation in P. aeruginosa infection, and that this is dependent upon production of TGF? and arginase-1. We will utilize a model of P. aeruginosa pneumonia in normal and genetically engineered mice to address 3 distinct aims.
Aim 1 will determine whether regulation of inflammation caused by P. aeruginosa lung infection is dependent upon alternative macrophage activation.
Aim 2 will address whether AAM regulation of T cell disposition can control inflammation and lung damage through the production of TGF?.
Aim 3 will determine whether arginase-1 expression by macrophages is required to prevent inflammation induced by P. aeruginosa pneumonia. Mouse models with genetically altered AAM, TGF? signaling, and macrophage-specific arginase-1 production will be used, along with adoptive transfer methodologies and complementary in vitro experiments. The impact of these alterations will be evaluated in terms of inflammation, classical macrophage function, and T cell subset activation and function to determine the important mechanisms employed by macrophages in regulating these responses. Highlighting the clinical relevance of this work is the use of the antimicrobial agent azithromycin as an immunomodulator in patients with CF. This drug has been shown to slow pulmonary function decline and decrease morbidity in CF patients infected with Pseudomonas, but the beneficial mechanistic effect is unknown. Recently it has been shown, in both in vitro and animal studies, that azithromycin polarizes macrophages to an alternative-like phenotype, dramatically increasing the expression of arginase-1. This data, along with the successful long-term use of azithromycin in patients with CF, make studying the role of alternative macrophage activation in response to Pseudomonas pneumonia attractive and likely to yield novel therapeutic targets for intervention to alter this destructive cycle of inflammation and airway damage.
Cystic fibrosis and other chronic lung diseases cause progressive, life-threatening lung destruction due in part to excessive inflammation with frequent exacerbations caused by repeated bacterial infections. This project will investigate the regulatory role that macrophages play in the immune response to Pseudomonas aeruginosa, one of the most common bacterial pathogens in these patients. This work will lead to the identification of therapeutic targets for intervention to delay the rate of pulmonary decline in these patients.
|Shirey, Kari Ann; Lai, Wendy; Pletneva, Lioubov M et al. (2014) Agents that increase AAM differentiation blunt RSV-mediated lung pathology. J Leukoc Biol 96:951-5|