Update on the role of alternatively activated macrophages in asthma

Abstract

Lung macrophages link innate and adaptive immune responses during allergic airway inflammatory responses. Alveolar macrophages (AMs) and interstitial macrophages are two different phenotypes that differentially exert immunological function under physiological and pathological conditions. Exposure to pathogen induces polarization of AM cells into classically activated macrophages (M1 cells) and alternatively activated macrophages (M2 cells). M1 cells dominantly express proinflammatory cytokines such as TNF-α and IL-1 β and induce lung inflammation and tissue damage. M2 cells are further divided into M2a and M2c subsets. M2a cells dominantly produce allergic cytokines IL-4 and IL-13, but M2c cells dominantly produce anti-inflammatory cytokine IL-10. M2a and M2c cells are differently involved in initiation, inflammation resolution, and tissue remodeling in the different stages of asthma. Microenvironment dynamically influences polarization of AM cells. Cytokines, chemokines, and immune-regulatory cells interplay and affect the balance between the polarization of M1 and M2 cells, subsequently influencing disease progression. Thus, modulation of AM phenotypes through molecular intervention has therapeutic potential in the treatment of asthma and other allergic inflammatory diseases. This review updated recent advances in polarization and functional specialization of these macrophage subtypes with emphasis on modulation of polarization of M2 cells in asthma of human subjects and animal models.

Keywords: M2 cells; alternatively activated macrophages; asthma; cytokines; macrophage polarization.

Figure 1

Schematic diagram of subtypes of lung macrophages during allergic immune responses after exposure to allergen. Notes: Exposure to allergens activates lung epithelial cells and other innate immune cells. The activated cells release a variety of cytokines and distinctly affect AM polarization and migration. Classically activated macrophages (M1 cells) can be activated by IFN-γ and LPS, inducing nonallergic immune responses through releasing TNF-α and IL-1 β. Alternatively, activated macrophages (M2 cells) are divided into M2a and M2c cells. M2a cells can be activated by IL-4, IL-13, and IL-33, inducing allergic immune responses through releasing IL-4 and IL-13. M2c cells can be activated by IL-10 and TGF-β, inducing lung inflammation resolution and tissue repair through releasing IL-10. Bone marrow-derived stromal cells and regulatory T cells also drive M2c cell polarization through IDO and IL-10. M2c cells have low activation markers and are more potent in phagocytosis of invading pathogens than other macrophage phenotypes. Abbreviations: AM, alveolar macrophage; LPS, lipopolysaccharide; IDO, indoleamine 2,3-dioxygenase.