Alveolar macrophages in tissue homeostasis, inflammation, and infection: evolving concepts of therapeutic targeting

Abstract

Alveolar macrophages (AMs) are the sentinel cells of the alveolar space, maintaining homeostasis, fending off pathogens, and controlling lung inflammation. During acute lung injury, AMs orchestrate the initiation and resolution of inflammation in order to ultimately restore homeostasis. This central role in acute lung inflammation makes AMs attractive targets for therapeutic interventions. Single-cell RNA-Seq and spatial omics approaches, together with methodological advances such as the generation of human macrophages from pluripotent stem cells, have increased understanding of the ontogeny, function, and plasticity of AMs during infectious and sterile lung inflammation, which could move the field closer to clinical application. However, proresolution phenotypes might conflict with proinflammatory and antibacterial responses. Therefore, therapeutic targeting of AMs at vulnerable time points over the course of infectious lung injury might harbor the risk of serious side effects, such as loss of antibacterial host defense capacity. Thus, the identification of key signaling hubs that determine functional fate decisions in AMs is of the utmost importance to harness their therapeutic potential.

The guardians of pulmonary harmony: alveolar macrophages orchestrating the symphony of lung inflammation and tissue homeostasis

“…Overall, we are just beginning to understand the immunometabolic properties of TR-AMs. Already known and yet-to-be-identified key metabolic regulations might pave the way for macrophage-targeted therapies in lung inflammation [ 96 ].…”

“…Identifying biomarkers and mechanisms of alveolar macrophage phenotype acquisition would allow us to enter new avenues for trait or outcome prediction and for the treatment of acute and chronic lung disease in humans. Putative targeted interventions involve actively reprogramming lung macrophages in a disease-, compartment- and disease course-specific manner to generate macrophage-based cell therapies and to use or target macrophage effector molecules to fine-tune host defence, inflammation resolution or lung repair processes [ 50 , 96 , 170 ].…”

Microbiota and Immunity during Respiratory Infections: Lung and Gut Affair

“…Different types of innate immune cells are present in the lung: alveolar macrophages (AMs) are the most representative ones and appear to be central in the pathogenesis of several respiratory tract infections, including Mtb, S. pneumoniae, rhinovirus, IV, and RSV [82]. AMs start the leukocyte recruitment and directly eliminate the pathogen using several pathogen-specific mechanisms, such as secretion of pro-inflammatory cytokines/chemokines (IL-6, IL-8, or CXCL10), initiation of type I IFN signaling, enhanced expression of pattern recognition receptors (PRR), together with inhibition of nuclear export of viral genome [83].…”

CHIPing away at immunity: the role of clonal hematopoiesis of indeterminate potential in bacterial pneumonia

“…Loss of function of Tet2 has been linked to an inflammatory phenotype in macrophages that contributes to cardiovascular disease ( 15 ). Since macrophages play an important role in the resolution of inflammation and return to homeostasis following lung injury ( 19 ), CHIP may also have a role in impaired pulmonary repair following infection. Another outstanding question relates to whether the mechanisms identified in Quin et al ( 13 ) also hold true for other pneumonias, for example, of viral etiology.…”