Alveolar macrophages and airway hyperresponsiveness associated with respiratory syncytial virus infection

Abstract

Respiratory syncytial virus (RSV) is a ubiquitous pathogen of viral bronchiolitis and pneumonia in children younger than 2 years of age, which is closely associated with recurrent wheezing and airway hyperresponsiveness (AHR). Alveolar macrophages (AMs) located on the surface of the alveoli cavity are the important innate immune barrier in the respiratory tract. AMs are recognized as recruited airspace macrophages (RecAMs) and resident airspace macrophages (RAMs) based on their origins and roaming traits. AMs are polarized in the case of RSV infection, forming two macrophage phenotypes termed as M1-like and M2-like macrophages. Both M1 macrophages and M2 macrophages are involved in the modulation of inflammatory responses, among which M1 macrophages are capable of pro-inflammatory responses and M2 macrophages are capable of anti-proinflammatory responses and repair damaged tissues in the acute and convalescent phases of RSV infection. Polarized AMs affect disease progression through the alteration of immune cell surface phenotypes as well as participate in the regulation of T lymphocyte differentiation and the type of inflammatory response, which are closely associated with long-term AHR. In recent years, some progress have been made in the regulatory mechanism of AM polarization caused by RSV infection, which participates in acute respiratory inflammatory response and mediating AHR in infants. Here we summarized the role of RSV-infection-mediated AM polarization associated with AHR in infants.

Cholinergic Polarization of Human Macrophages

“…Similarly, hepatitis C virus core protein engagement with Toll-like receptor 2 of macrophages inhibits M2a, M2b, and M2c macrophage polarization [44]. Furthermore, in the case of a respiratory syncytial virus (RSV) infection, the polarization of alveolar macrophages occurs as a result of cytokines (IFN and GM-CSF), intercellular communication via the Notch-Jagged pathway, and RSV's direct activation signal [45]. Interestingly, the soluble spike protein of SARS-CoV-2 has recently gained prominence as a potential culprit in the deregulation of macrophage polarization via the α7-nAChR in COVID-19 [46].…”

Reshaping Our Knowledge: Advancements in Understanding the Immune Response to Human Respiratory Syncytial Virus

“…Under physiological conditions, there are two subpopulations of pulmonary macrophages: alveolar macrophages (AMs) at the surface of alveolar cells and interstitial macrophages (IMs) in the pulmonary stromata. During inflammatory states, AMs are identified as the macrophages residing in the airspace (RAMs), while IMs migrate toward the alveoli cavity and transform into the recruited airspace macrophages (RecAMs) [ 87 ]. Depending on the microenvironment, both RAMs and RecAMs can be polarized toward two different phenotypes: the pro-inflammatory phenotype M1 promotes inflammation and tissue damage, and the anti-inflammatory phenotype M2 contrasts inflammation and promotes tissue repair [ 87 ].…”

“…During inflammatory states, AMs are identified as the macrophages residing in the airspace (RAMs), while IMs migrate toward the alveoli cavity and transform into the recruited airspace macrophages (RecAMs) [ 87 ]. Depending on the microenvironment, both RAMs and RecAMs can be polarized toward two different phenotypes: the pro-inflammatory phenotype M1 promotes inflammation and tissue damage, and the anti-inflammatory phenotype M2 contrasts inflammation and promotes tissue repair [ 87 ]. RSV can trigger AMs polarization through direct invasion, cytokines, and intercellular communication signaling.…”

“…Concerning cytokines, IFN-γ promotes M1 polarization, and this mechanism’s magnitude is age-related. In fact, in adults, CD4 T cells express a high level of sialic acid-binding immunoglobulin agglutinin (Siglec-1) ligand CD43 that antagonize the monocytes signaling for CD4 T cells IFN-γ release [ 87 , 88 ]. Another age-related mechanism is the production of IFN-I by AMs during the inflammatory phase.…”

“…Another age-related mechanism is the production of IFN-I by AMs during the inflammatory phase. Such production would be extremely minor in children, thereby reducing the capacity for viral clearance [ 87 ]. These two differences partly explain the different susceptibility of children and adults to developing RSV severe infections.…”