Extracellular vesicles as carriers for noncoding RNA-based regulation of macrophage/microglia polarization: an emerging candidate regulator for lung and traumatic brain injuries

Abstract

Macrophage/microglia function as immune defense and homeostatic cells that originate from bone marrow progenitor cells. Macrophage/microglia activation is historically divided into proinflammatory M1 or anti-inflammatory M2 states based on intracellular dynamics and protein production. The polarization of macrophages/microglia involves a pivotal impact in modulating the development of inflammatory disorders, namely lung and traumatic brain injuries. Recent evidence indicates shared signaling pathways in lung and traumatic brain injuries, regulated through non-coding RNAs (ncRNAs) loaded into extracellular vesicles (EVs). This packaging protects ncRNAs from degradation. These vesicles are subcellular components released through a paracellular mechanism, constituting a group of nanoparticles that involve exosomes, microvesicles, and apoptotic bodies. EVs are characterized by a double-layered membrane and are abound with proteins, nucleic acids, and other bioactive compounds. ncRNAs are RNA molecules with functional roles, despite their absence of coding capacity. They actively participate in the regulation of mRNA expression and function through various mechanisms. Recent studies pointed out that selective packaging of ncRNAs into EVs plays a role in modulating distinct facets of macrophage/microglia polarization, under conditions of lung and traumatic brain injuries. This study will explore the latest findings regarding the role of EVs in the progression of lung and traumatic brain injuries, with a specific focus on the involvement of ncRNAs within these vesicles. The conclusion of this review will emphasize the clinical opportunities presented by EV-ncRNAs, underscoring their potential functions as both biomarkers and targets for therapeutic interventions.

Keywords: extracellular vesicles; lung brain injury; macrophage/microglia polarization; noncoding RNA; traumatic brain injury.

Figure 1

The underlying action of extracellular vesicle-noncoding RNA on the modulation of macrophage/microglia polarization in traumatic brain injury. Extracellular vesicles (EVs), encompassing exosomes, microvesicles, and apoptotic bodies, form a diverse category of lipid bilayer-encased structures released by nearly all cells. They play crucial roles in facilitating intercellular communication. These EVs carry non-coding RNAs (ncRNAs) that can either promote or inhibit the polarization of M2 microglia. Examples of such ncRNAs include circ-Scmh1, lncRNA 4933431K23Rik, miR-216a-5p, miR-873a-5p, miR-9-5p, miR-181b, miR-210, miR−124, and miR-21-5p. These ncRNA-containing EVs have been identified across a spectrum of cell types, including neurons, astrocytes, microglia, and stem cells derived from various tissues such as bone marrow and adipose tissue.

Figure 2

The underlying action of extracellular vesicle-noncoding RNA on the modulation of macrophage/microglia polarization in lung injury. Extracellular vesicles (EVs) harboring non-coding RNAs (ncRNAs) capable of either promoting or inhibiting M2 microglia polarization have been recognized. Examples of these ncRNAs include lncRNA Lncenc1, miR-223-3p, miR-155, miR-30d-5p, miR-221, miR-320a, miR-210-3p, miR-384-5p, miR−92a-3p, miR-451, miR-181a-5p, miR-21a 5p, miR‐223, and LncRNA HCG18. These EVs have been isolated from diverse cellular origins, including macrophages, bronchoalveolar lavage fluid, mouse blood, epithelial cells, human plasma, polymorphonuclear neutrophils, and stem cells derived from tissues such as bone marrow and adipose tissue. Among these non-coding RNAs, those released by stem cells can promote the differentiation of M2 macrophages, thereby improving the prognosis of lung injury.