Phagocytosis of microparticles by alveolar macrophages during acute lung injury requires MerTK

Abstract

Microparticles are a newly recognized class of mediators in the pathophysiology of lung inflammation and injury, but little is known about the factors that regulate their accumulation and clearance. The primary objective of our study was to determine whether alveolar macrophages engulf microparticles and to elucidate the mechanisms by which this occurs. Alveolar microparticles were quantified in bronchoalveolar fluid of mice with lung injury induced by LPS and hydrochloric acid. Microparticle numbers were greatest at the peak of inflammation and declined as inflammation resolved. Isolated, fluorescently labeled particles were placed in culture with macrophages to evaluate ingestion in the presence of endocytosis inhibitors. Ingestion was blocked with cytochalasin D and wortmannin, consistent with a phagocytic process. In separate experiments, mice were treated intratracheally with labeled microparticles, and their uptake was assessed though microscopy and flow cytometry. Resident alveolar macrophages, not recruited macrophages, were the primary cell-ingesting microparticles in the alveolus during lung injury. In vitro, microparticles promoted inflammatory signaling in LPS primed epithelial cells, signifying the importance of microparticle clearance in resolving lung injury. Microparticles were found to have phosphatidylserine exposed on their surfaces. Accordingly, we measured expression of phosphatidylserine receptors on macrophages and found high expression of MerTK and Axl in the resident macrophage population. Endocytosis of microparticles was markedly reduced in MerTK-deficient macrophages in vitro and in vivo. In conclusion, microparticles are released during acute lung injury and peak in number at the height of inflammation. Resident alveolar macrophages efficiently clear these microparticles through MerTK-mediated phagocytosis.

The role of microvesicles and its active molecules in regulating cellular biology

“…When circulating MVs are reduced to the normal level, some physiological changes in the body can be alleviated and improved to some extent, such as inflammation injury, and blood hypercoagulability. MerTK‐mediated alveolar macrophage phagocytosis can clear MVs in the lungs, which could alleviate pulmonary inflammatory damage . Del‐1 mediates the clearance of PMVs through endothelial cells, which can reduce the cytokine response of synovial fibroblasts and stimulate haematopoietic cells .…”

Cholesterol-25-hydroxylase promotes efferocytosis and resolution of lung inflammation

“…The latter differentiate after arrival into macrophages with distinct transcriptional and metabolic profiles from their tissue-resident counterparts (1). Resident and recruited macrophages, instructed by an evolving cocktail of signals in the local inflammatory milieu, then drive resolution through phagocytic clearance of apoptotic cells (ACs) (i.e., efferocytosis) (2,3). Binding and internalization of ACs engages antiinflammatory programs in macrophages (4,5) and also feeds forward to sustain efferocytosis through activation of liver X receptor (LXR) and other transcription factors that upregulate efferocytic receptors, such as MERTK (6,7).…”

Potential Involvement of Platelet-Derived Microparticles and Microparticles Forming Immune Complexes during Monocyte Activation in Patients with Systemic Lupus Erythematosus

“…Therefore, similar to ACs, MPs are associated with different autoantigens, such as autoantigens derived from nucleosomes ( 5 ) and have a broad spectrum of effects on immune responses ( 6 ). For example, monocytes and macrophages seem to play critical roles in the clearance of these structures ( 7 – 9 ), and monocyte-derived MPs induced reactive oxygen species (ROS) production, the release of cytokines, such as IL-6, and NF-κB activation in human monocytes and macrophages ( 10 ). Additionally, MPs from apoptotic neutrophils from healthy donors together with raised IFN-α concentrations induced the secretion of the pro-inflammatory cytokines IL-6, IL-8, and TNF-α in monocytes from the same donors, and also macrophage polarization was shifted toward a more inflammatory type after the same treatment ( 11 ).…”