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. 2023 Apr 19;14:1152881. doi: 10.3389/fimmu.2023.1152881

Figure 3.

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.