The roles of long noncoding RNA-mediated macrophage polarization in respiratory diseases

Abstract

Macrophages play an essential role in maintaining the normal function of the innate and adaptive immune responses during host defence. Macrophages acquire diverse functional phenotypes in response to various microenvironmental stimuli, and are mainly classified into classically activated macrophages (M1) and alternatively activated macrophages (M2). Macrophage polarization participates in the inflammatory, fibrotic, and oncogenic processes of diverse respiratory diseases by changing phenotype and function. In recent decades, with the advent of broad-range profiling methods such as microarrays and next-generation sequencing, the discovery of RNA transcripts that do not encode proteins termed "noncoding RNAs (ncRNAs)" has become more easily accessible. As one major member of the regulatory ncRNA family, long noncoding RNAs (lncRNAs, transcripts >200 nucleotides) participate in multiple pathophysiological processes, including cell proliferation, differentiation, and apoptosis, and vary with different stimulants and cell types. Emerging evidence suggests that lncRNAs account for the regulation of macrophage polarization and subsequent effects on respiratory diseases. In this review, we summarize the current published literature from the PubMed database concerning lncRNAs relevant to macrophage polarization and the underlying molecular mechanisms during the occurrence and development of respiratory diseases. These differentially expressed lncRNAs are expected to be biomarkers and targets for the therapeutic regulation of macrophage polarization during disease development.

Keywords: M1/M2 polarization; long noncoding RNAs; lung cancer; macrophages; respiratory diseases.

Figure 1

A schematic summary of the role of various long non-coding RNAs in modulating macrophage polarization involved in respiratory diseases.

Figure 2

The role of macrophages and associated lncRNAs in allergic asthma. Antigen-presenting cells (APCs) identify allergens and initiate the allergic response. Under this condition, naïve CD4+ T cells differentiate into Th2 cells. Th2 cells secreting IL-4 induce M2 macrophage polarization. Lnc-BAZ2B promotes M2 macrophage activation by stabilizing BAZ2B pre-mRNA, thereby promoting IRF4 expression and chemokines secretion, leading to mucus hypersecretion and eosinophil infiltration in allergic children. PTPRE-AS1 is selectively expressed in IL-4–stimulated M2 macrophages. PTPRE-AS1 binds WDR5 directly, modulating H3K4me3 of the PTPRE promoter to regulate PTPRE-dependent signaling during M2 macrophage activation and protects against pulmonary allergic inflammation. LncRNA AK085865 promotes M2 macrophages activation and M2 macrophages promote the differentiation of innate lymphoid cells progenitor (ILCP) into type II innate lymphoid cells (ILC2s), thus aggravate Type 2 immune response. Non-Th2 asthma (i.e., neutrophilic asthma), by contrast, is driven by M1 macrophages or Th1/Th17 lymphocytes through the production of high levels of proinflammatory Th1 cytokines (e.g., IL-6, IL-1β, and TNF-α) and chemokines (e.g., CCL2 and CCL5), contributing to neutrophilic infiltration and airway inflammation.

Figure 3

The role of macrophages and MIR155HG in chronic obstructive pulmonary disease (COPD). Tobacco smoke or toxic particles cause airway inflammation and airway remodelling. Macrophage polarization plays a key role. M1 macrophages secrete inflammatory cytokines and chemokines, promoting neutrophil recruitment and augmenting airway inflammation. MIR155HG indirectly regulate NF-κB signaling activity by interacting with the p65-p50 complex, resulting in M1 macrophages activation accompanied by enhanced proinflammatory cytokine release (TNF-α, IL-1β and IL-12). M2 macrophage-induced TGF-β, Fizz1 and Ym1 are involved in epithelial mesenchymal transformation (EMT) and extracellular matrix dynamics, and arginine accelerates collagen synthesis, which leads to fibrosis.

Figure 4

The role of macrophages and associated lncRNAs in ALI/ARDS. In response to various physicochemical stimuli, M1 macrophages release various proinflammatory cytokines at the site of inflammation and then recruit neutrophils from the circulation into the lung and alveolar spaces. Excess accumulation of proinflammatory factors and neutrophils promotes the progression of inflammation and lung injury. LincRNA-p21 contributes to LPS-induced M1 activation by promoting the ubiquitination of IκBα, activating NF-κB as well as promoting p65 nuclear translocation. MALAT1 promotes the expression of C-type lectin domain family 16, member A (Clec16a) in nucleus, which is required for the proinflammatory activation of M1 macrophages. After the elimination of the trigger, macrophages changed from the M1 to the M2 phenotype, and ALI/ARDS entered the recovery stage. M2 macrophages play an important role in inflammation resolution and lung tissue repair by limiting the levels of proinflammatory cytokines and enhancing the production of anti-inflammatory cytokines. MALAT1 regulation of M2 activation of macrophages is dependent on glucose metabolism. Both mitochondrial pyruvate carriers (MPC)1 and MPC2 are upregulated by IL-4. IL-4 downregulates MALAT1 expression, and MALAT1 knockdown enhances the expression of MPC1 and MPC2, therefore regulating glucose-derived mitochondrial oxidative phosphorylation (OxPhos), which is essential to M2 macrophage polarization.