Lung macrophages play important roles in the maintenance of homeostasis, pathogen clearance and immune regulation. The different types of pulmonary macrophages and their roles in lung diseases have attracted attention in recent years. Alveolar macrophages (AMs), including tissue-resident alveolar macrophages (TR-AMs) and monocyte-derived alveolar macrophages (Mo-AMs), as well as interstitial macrophages (IMs) are the major macrophage populations in the lung and have unique characteristics in both steady-state conditions and disease states. The different characteristics of these three types of macrophages determine the different roles they play in the development of disease. Therefore, it is important to fully understand the similarities and differences among these three types of macrophages for the study of lung diseases. In this review, we will discuss the physiological characteristics and unique functions of these three types of macrophages in acute and chronic lung diseases. We will also discuss possible methods to target macrophages in lung diseases.

Acute lung injury (ALI) is a pulmonary disorder, which can result in fibrosis of the lung tissues. Recently, mesenchymal stem cell (MSC) has become a novel therapeutic method for ALI. However, the potential mechanism by which MSC regulates the progression of ALI remains blurry. The present study focused on investigating the mechanism underneath MSC-reversed lung injury and fibrosis. At first, we determined that coculture with MSC led to the inactivation of NF-κB signaling and therefore suppressed hedgehog pathway in LPS-treated MLE-12 cells. Besides, we confirmed that MSC-exosomes were responsible for the inhibition of EMT process in LPS-treated MLE-12 cells through transmitting miRNAs. Mechanism investigation revealed that MSC-exosome transmitted miR-182-5p and miR-23a-3p into LPS-treated MLE-12 cells to, respectively, target Ikbkb and Usp5. Of note, Usp5 interacted with IKKβ to hamper IKKβ ubiquitination. Moreover, co-inhibition of miR-182-5p and miR-23a-3p offset the suppression of MSC on EMT process in LPS-treated MLE-12 cells as well as in LPS-injured lungs of mice. Besides, the retarding effect of MSC on p65 nuclear translocation was also counteracted after co-inhibiting miR-182-5p and miR-23a-3p, both in vitro and in vivo. In summary, MSC-exosome transmitted miR-23a-3p and miR-182-5p reversed the progression of LPS-induced lung injury and fibrosis through inhibiting NF-κB and hedgehog pathways via silencing Ikbkb and destabilizing IKKβ.

Acute respiratory distress syndrome (ARDS) develops rapidly and has a high mortality rate. Survivors usually have low quality of life. Current clinical management strategies are respiratory support and restricted fluid input, and there is no suggested pharmacological treatment. Mesenchymal stromal cells (MSCs) have been reported to be promising treatments for lung diseases. MSCs have been shown to have a number of protective effects in some animal models of ARDS by releasing soluble, biologically active factors. In this review, we will focus on clinical progress in the use of MSCs as a cell therapy for ARDS, which may have clinical implications during the coronavirus disease 2019 (COVID-19) pandemic.

Macrophages are highly heterogeneous immune cells that fulfill tissue-specific functions. Tissue-derived signals play a critical role in determining macrophage heterogeneity. However, these signals remain largely unknown. The BMP receptor activin receptor–like kinase 1 (ALK1) is well known for its role in blood vessel formation; however, its role within the immune system has never been revealed to our knowledge. Here, we found that BMP9/BMP10/ALK1 signaling controlled the identity and self-renewal of Kupffer cells (KCs) through a Smad4-dependent pathway. In contrast, ALK1 was dispensable for the maintenance of macrophages located in the lung, kidney, spleen, and brain. Following ALK1 deletion, KCs were lost over time and were replaced by monocyte-derived macrophages. These hepatic macrophages showed significantly reduced expression of the complement receptor VSIG4 and alterations in immune zonation and morphology, which is important for the tissue-specialized function of KCs. Furthermore, we found that this signaling pathway was important for KC-mediated Listeria monocytogenes capture, as the loss of ALK1 and Smad4 led to a failure of bacterial capture and overwhelming disseminated infections. Thus, ALK1 signaling instructs a tissue-specific phenotype that allows KCs to protect the host from systemic bacterial dissemination.

Pulmonary infections are common respiratory diseases caused by a variety of pathogens, some of which can lead to epidemics. When they progress to acute lung injury or acute respiratory distress syndrome, the mortality rate is high and effective treatment options are lacking. Macrophages play a crucial role in the development and progression of lung injury, and serve as core components of immune regulation in the lungs. Therefore, regulation of macrophages to intervene in the progression of infection-induced lung injury is a promising research direction. However, the existence of different macrophage subsets and their inherent heterogeneity has led to the failure of many studies to achieve effective results, thereby limiting their clinical applications. We believe that interventions targeting macrophages must consider factors, such as macrophage subsets, timing of interventions, patients’ varying immune states, and clinical stages, rather than simply focusing on regulating their phenotypes. This distinction is the key to the success of macrophage-targeted therapies. In this review, we summarize the characteristics of two distinct macrophage subpopulations, lung-tissue-resident alveolar macrophages and monocyte-derived macrophages, along with intervention strategies and research progress at various time points, with the aim of providing insights and directions for future research.

Hou F, et al. Immune Netw. 2023 Feb;23(3):e24. https://doi.org/10.4110/in.2023.23.e24