Alternative Macrophage Activation Is Increased in Asthma

Abstract

The immune responses of type 2 T helper cells (Th2) play an important role in asthma and promote the differentiation of alternatively activated (M2) macrophages. M2 macrophages have been increasingly understood to contribute to Th2 immunity. We hypothesized that M2 macrophages are altered in asthma and modulate Th2 responses. The aim of this study was to characterize the phenotype and function of human monocyte-derived M2 and bronchoalveolar lavage fluid (BALF) macrophages from healthy control subjects and subjects with asthma. Phenotypic characteristics and effector function of M2 macrophages were examined using monocyte-derived and BALF macrophages obtained from subjects with asthma (n = 28) and healthy volunteers (n = 9) by flow cytometry and quantitative PCR. Resting monocyte-derived (M0) and M2 macrophages were generated by the addition of macrophage colony-stimulating factor or macrophage colony-stimulating factor plus IL-4, respectively. M2 macrophage cytokine expression and their impact on dendritic and CD4 T cell activation were examined in vitro. High levels of CD206 and major histocompatibility complex class II expression identify macrophages with an M2 phenotype that are increased 2.9-fold in the BALF of subjects with asthma compared with control subjects. M2 macrophages have elevated IL-6, IL-10, and IL-12p40 production compared with conventional macrophages and modulate dendritic and CD4 T cell interactions. Histamine receptor 1 and E-cadherin expression identify M2 macrophage subsets associated with increased airflow obstruction. M2 macrophages have a distinct cell surface and effector phenotype and are found in increased numbers in subjects with asthma. These findings suggest that M2 macrophages may play an important role in allergic asthma through their bidirectional interactions with immune and structural cells, and inflammatory mediators.

Estrogen Signaling Contributes to Sex Differences in Macrophage Polarization during Asthma

“…Others have shown that M2-activated alveolar macrophages are critical in recruiting inflammatory cells like eosinophils and in secreting factors that promote tissue remodeling and fibrosis in animal models of asthma (19, 21, 46). Likewise, the sputum and airway walls of asthmatic patients is rich with M2-polarized alveolar macrophages and their expression of M2 markers like CD206 and CCL17 positively correlates with asthma severity (47, 48). Inhaled glucocorticoid treatment is a mainstay therapy used to dampen inflammatory gene expression by leukocytes, including macrophages, in asthmatic patients (49).…”

“…We were especially interested in the early cellular and molecular events that shape the inflammatory response in the allergic lungs. However, it is clear that M2 macrophages are enriched and persist chronically in the lungs of people with asthma (18, 47, 54–58). …”

Secreted PLA2 group X orchestrates innate and adaptive immune responses to inhaled allergen

“…Our data indicate that sPLA 2 -X influences the innate immune responses through activation of macrophages and polarization of both resident and newly recruited macrophages toward an M2 phenotype expressing the transferrin (CD71) and mannose (CD206) receptors. Although M2-polarized macrophages function during the resolution phase of inflammation (37), studies implicate a pathogenic role for M2 macrophages in asthma (67). Prior studies have also demonstrated that sPLA 2 -V is necessary for the development of allergic inflammation in the HDM (68) and OVA/alum (69) models of allergic airways disease, and that while sPLA 2 -V is involved in maturation and antigen processing in DCs (68), macrophages expressing sPLA 2 -V are sufficient to transfer antigen sensitization mice (20).…”

Increased intermediate M1‐M2 macrophage polarization and improved cognition in mild cognitive impairment patients on ω‐3 supplementation

“…The M1 status is associated with inflammatory conditions and is mitigated by v‐3s (34). Alternative activation of macrophages to M2 status has a bifunctional role in diseases, such as asthma (35, 36) and pancreatic fibrosis (37). We speculate that the outcome of immune therapy for patients with MCI depends in part on modulating inflammatory M1 (red zone) or anti‐inflammatory M2 (white zone) macrophages at baseline to a proresolution and prophagocytic intermediate M1‐M2 (green zone) phenotype.…”