The role of lung macrophages in acute respiratory distress syndrome

Abstract

Acute respiratory distress syndrome (ARDS) is an acute and diffuse inflammatory lung injury in a short time, one of the common severe manifestations of the respiratory system that endangers human life and health. As an innate immune cell, macrophages play a key role in the inflammatory response. For a long time, the role of pulmonary macrophages in ARDS has tended to revolve around the polarization of M1/M2. However, with the development of single-cell RNA sequencing, fate mapping, metabolomics, and other new technologies, a deeper understanding of the development process, classification, and function of macrophages in the lung are acquired. Here, we discuss the function of pulmonary macrophages in ARDS from the two dimensions of anatomical location and cell origin and describe the effects of cell metabolism and intercellular interaction on the function of macrophages. Besides, we explore the treatments for targeting macrophages, such as enhancing macrophage phagocytosis, regulating macrophage recruitment, and macrophage death. Considering the differences in responsiveness of different research groups to these treatments and the tremendous dynamic changes in the gene expression of monocyte/macrophage, we discussed the possibility of characterizing the gene expression of monocyte/macrophage as the biomarkers. We hope that this review will provide new insight into pulmonary macrophage function and therapeutic targets of ARDS.

Keywords: Acute respiratory distress syndrome; Alveolar macrophages; Biomarker; Inflammation; Monocyte-derived macrophages; Therapy.

Fig. 1

The function of pulmonary macrophages and their interactions with other cells. At steady state, resident alveolar macrophages (RAMs) maintain the hyporesponsive state affected by various cytokines and promote the differentiation of CD4⁺ T cells into Treg cells through secreting transforming growth factor-β (TGF-β) and retinal dehydrogenase (RALDH). Likewise, interstitial macrophages can facilitate the differentiation of CD4 + T cells into Treg cells. In inflammation, RAMs secrete chemokines to recruit neutrophils and monocytes. Neutrophil extracellular traps (NETs) can lead to the pyroptosis of AMs. Monocytes can differentiate into pulmonary vascular macrophages, interstitial macrophages and RECAMs. Recruited alveolar macrophages (RECAMs) secrete inflammatory factors leading to alveolar epithelial cell apoptosis and inhibiting the differentiation of Treg cells. C-type lectin-like 2 (CLEC-2) expressed by platelets interacted with RECAMs to inhibit the activities of chemokines. ATI alveolar type I cell, ATII alveolar type II cell, GM-CSF granulocyte-macrophage colony stimulating factor, L-10 interleukin-10, IL-1 interleukin-1, Treg regulatory T cells, HMGB1 high mobility group protein-1, MMP12 matrix metalloproteinase-12, TRAIL tumor necrosis factor related apoptosis-inducing ligand, DR-5 death receptor-5