Pulmonary Collectins, Arginases and Inducible NOS Regulate Nitric Oxide-Mediated Antibacterial Defense and Macrophage Polarization

ABSTRACT

Nitric oxide (NO) is important for combating bacterial infections in the lungs. Levels of NO in the lungs are regulated by L-arginine, arginases (ARG) and NO synthases (NOS). Expression levels of ARG and inducible NOS (iNOS) vary among different types of macrophages (M0, M1, M2). Several events including infection, inflammation and tissue repair/resolution polarize macrophages (M0) into either M1 or M2 types. In general, M1 and M2 macrophages express high levels of iNOS and ARG, respectively. Classically activated M1 macrophages that are related to killing intracellular pathogens release T_H1 type cytokines (e.g., IFNγ, TNFα, IL-1β, IL-12) whereas the alternatively activated M2 macrophages that are involved in humoral immune response release T_H2 type cytokines (e.g., IL-4, IL-10). Based on the activating cytokines, M2 macrophages are further subdivided into M2a, M2b or M2c. Macrophage activation and polarization are also regulated by other soluble proteins such as the innate immune pattern-recognition collectins (collagenous lectins), surfactant protein (SP)-A and SP-D. These soluble defense molecules are known to recognize microbes, and agglutinate and/or form immune complexes to enhance pathogen clearance by macrophages. In the absence of SP-D, mouse alveolar macrophages show exaggerated M1-like phenotype. Certain microbial pathogens also modulate lung environment or macrophages to evade the nitric oxide-mediated immune response. In summary, interplay among microbes, cytokines, ARG, NOS and collectins regulate alveolar macrophage types and NO production in the lungs. The balance among these molecules appears to help eliminate microbial pathogens form the lungs with minimal inflammation.

Keywords:

Collectins , surfactant proteins SP-A , P-D , arginases , NOS , macrophage polarization , nitric oxide .