Alternative macrophage activation in acute Pseudomonas pneumonia

描述（由申请人提供）：选择性巨噬细胞激活调节对病原生物的炎症反应。迄今为止，大多数研究都描述了它们在th2型免疫反应中的作用。选择性活化的巨噬细胞（AAM）已被证明可以抑制经典活化的巨噬细胞的增殖和功能，并通过产生II型细胞因子转化生长因子(TGF)-¿和精氨酸酶-1来抑制T细胞介导的免疫反应。精氨酸酶-1和TGF -1的主要功能是协调重塑和修复机制，在控制肺稳态和抑制炎症方面也很重要。AAM在调节肺细胞外革兰氏阴性细菌感染的炎症反应中的功能尚未被表征。了解AAM在这种情况下的作用对于提高我们对影响囊性纤维化（CF）和其他慢性肺部炎症患者的免疫机制的理解至关重要。CF导致进行性、危及生命的肺损伤，很大程度上是由于铜绿假单胞菌感染引起的反复、失调的炎症反应。因此，这项工作将解决交替激活的假设

DESCRIPTION (provided by applicant): 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.