Macrophages Orchestrate Airway Inflammation, Remodeling, and Resolution in Asthma

Abstract

Asthma is a heterogenous chronic inflammatory lung disease with endotypes that manifest different immune system profiles, severity, and responses to current therapies. Regardless of endotype, asthma features increased immune cell infiltration, inflammatory cytokine release, and airway remodeling. Lung macrophages are also heterogenous in that there are separate subsets and, depending on the environment, different effector functions. Lung macrophages are important in recruitment of immune cells such as eosinophils, neutrophils, and monocytes that enhance allergic inflammation and initiate T helper cell responses. Persistent lung remodeling including mucus hypersecretion, increased airway smooth muscle mass, and airway fibrosis contributes to progressive lung function decline that is insensitive to current asthma treatments. Macrophages secrete inflammatory mediators that induce airway inflammation and remodeling. Additionally, lung macrophages are instrumental in protecting against pathogens and play a critical role in resolution of inflammation and return to homeostasis. This review summarizes current literature detailing the roles and existing knowledge gaps for macrophages as key inflammatory orchestrators in asthma pathogenesis. We also raise the idea that modulating inflammatory responses in lung macrophages is important for alleviating asthma.

Keywords: asthma; inflammation; macrophages; remodeling.

Figure 1

Macrophages contribute to asthma pathogenesis. Dysfunctional macrophages in asthma can contribute to enhanced immune cell responses, increased remodeling, and decreased clearance of inhaled pathogens and dead cells leading to persistent inflammation and asthma severity. Created with Biorender on 13 June 2023.

Figure 2

Macrophages contribute to both inflammation and inflammatory resolution. In inflammatory conditions, macrophages produce mediators such as TNF-α, IL-1β, and MMPs that lead to lung structural cell damage and remodeling. Dysfunctional efferocytosis leads to persistence of necrotic cells in lung tissue that release damage signals and further enhance inflammation. Macrophages contribute to inflammatory resolution by secreting mediators such as IL-10 and TGFβ, to repair lung structural integrity and by engulfing apoptotic cells to reduce inflammation. Created with Biorender on 13 June 2023.

Figure 3

Macrophages play a key role in removing inhaled viruses and bacteria from the airways. Viruses (rhinovirus and RSV) and bacteria (Staphylococcus aureus, non-typeable Haemophilus influenzae, and Moraxella catarrhalis) can augment macrophage polarization to heighten type 1, 2, and 17 inflammation. These responses are mediated through intracellular (RIG-1, TLR3, and TLR9) and extracellular (TLR2 and TRL4) pattern recognition receptors. Created with Biorender on 13 June 2023.