Role of macrophages in pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary vascular disease characterized by progressive pulmonary artery pressure elevation, increased pulmonary vascular resistance and ultimately right heart failure. Studies have demonstrated the involvement of multiple immune cells in the development of PAH in patients with PAH and in experimental PAH. Among them, macrophages, as the predominant inflammatory cells infiltrating around PAH lesions, play a crucial role in exacerbating pulmonary vascular remodeling in PAH. Macrophages are generally polarized into (classic) M1 and (alternative) M2 phenotypes, they accelerate the process of PAH by secreting various chemokines and growth factors (CX3CR1, PDGF). In this review we summarize the mechanisms of immune cell action in PAH, as well as the key factors that regulate the polarization of macrophages in different directions and their functional changes after polarization. We also summarize the effects of different microenvironments on macrophages in PAH. The insight into the interactions between macrophages and other cells, chemokines and growth factors may provide important clues for the development of new, safe and effective immune-targeted therapies for PAH.

Keywords: Pulmonary arterial hypertension; inflammatory response; macrophage microenvironment; macrophages; vascular remodeling.

Figure 1

Schematic diagram of macrophage sources, distribution and their activation. Macrophages are derived from bone marrow and embryonic stem cells, and some bone marrow-derived monocytes subsequently flow into tissues to develop into tissue-resident macrophages together with embryonic hepatocytes and yolk sac cells, and specifically differentiate into different functional macrophages at different sites. They have in common that both can polarize into pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. M1-type macrophages are activated by TLRs ligands and involve several transcription factors, such as NF-κB, STAT1, STAT5, IRF3, IRF5 and HIF-1α, while releasing pro-inflammatory and chemokines including TNF-α, IL-1α, IL-1β M2 macrophages activate transcription factors including STAT3, STAT6, IRF4, KLF4, JMJD3, PPARδ, PPARγ and release anti-inflammatory substances, cytokines and chemokines including IL-10, TGF-β, CCL17, CCL18 and CCL22, which promote tissue repair and regeneration, immunosuppression.

Figure 2

Diagram of PAH pathological mechanism. Three classical pathways; ET-1 binds to ETA and ETB receptors to promote intracellular Ca²⁺ release and Ca²⁺ channel opening, leading to increased intracellular Ca²⁺ and vascular remodeling; prostacyclin binds to GPCR and IP receptors, activating adenylate cyclase, converting ATP to cAMP and inhibiting cell proliferation by activating PKA and Epac; NO binds to GC, converting GTP to cGMP, thereby activating downstream PKG and causing vascular diastole. Immune cells and pulmonary hypertension, DCs stimulate T cell activation, T cells participate in pulmonary vascular remodeling by producing IL, TNF-α, IFN-γ, B cells participate in pulmonary vascular remodeling by over-secreting antibodies, cytokines, etc. Mast cells participate in the development of PAH by producing large amounts of IL-6, while reducing IL-6 production or inhibiting mast cell activation can reduce B lymphocyte production and can alleviate PAH. EC damages will release microvesicles, which contain miRs, and others, these MVs will stimulate macrophages to secrete cytokine such as TGF-β, and then stimulate PASMC proliferation.

Figure 3

Schematic diagram of the 5 important factors affecting the macrophage microenvironment. Lipid metabolism: monocrotaline induces an increase in body fatty acids and a decrease in fatty acid oxidation. Hypoxic environment: 5-lipoxygenase (5-LO) activation metabolizes leukotriene B4 (LTB4) to exacerbate ROS toxicity in mitochondria; Rho kinase signaling pathway activates TGF-β and causes vasoconstriction. Amino acid metabolism: two related transcriptional co-activators of Hippo signaling pathway, YAP/TAZ, can activate GLS enzymes and promote glutamine metabolism and TCA cycle disorder; arginine can generate citrulline in response to iNOS to participate in urea cycle and promote smooth muscle cell proliferation; methionine can induce elevated iNOS activity and increased TNF-α release, thus causing macrophages to M1 direction of polarization. Pro-inflammatory and anti-inflammatory factors: Inflammatory factors and chemokines secreted by immune cells are involved in the regulation of their respective inflammatory pathways, thus promoting or suppressing the inflammatory response. For example, IL-10 activates JAK1 and TYK2 phosphorylation and thereby activates the STAT3 pathway. Viral infection: Angiotensin-converting enzyme-2 (ACE2) receptor mediates the entry of SARS-CoV-2 virus via transmembrane protease serine 2 (TMPRSS2). On the one hand, the increase in free DABK content in the presence of decreased ACE2 function activates B1 receptors and also induces NO pathways to trigger inflammation; on the other hand, the virus attacks the body’s immune function through DNA replication, thus aggravating the body’s immune deficiency. Thus, these factors affecting the macrophage microenvironment can worsen the PAH process when they are deregulated.