The ACE2-Ang-(1‑7)-Mas Axis Modulates M1/M2 Macrophage Polarization to Relieve CLP-Induced Inflammation via TLR4-Mediated NF-кb and MAPK Pathways

Abstract

has been identified as an important anti-inflammatory and anti-fibrotic factor. This study determined how the ACE2-Ang-(1-7)-Mas axis affected M1/ M2 macrophage polarization and thus contributed to anti-inflammatory processes in the cecal ligation and puncture (CLP)-induced inflammation model. Materials and Methods: ELISA, western blotting, and qRT-PCR were used to verify that Ang-(1-7) decreased the expression of pro-inflammatory cytokines and increased anti-inflammatory cytokines. The differentiation of M1/M2 macrophages was assessed by flow cytometry for assessing the cell-surface markers, CD86 and CD206. The related key receptors and pathways were analyzed by Western blotting, qRT-PCR, and immunofluorescence. CLP-induced inflammatory mice models were used for in vivo studies. Hematoxylin and eosin and immunohistochemical and immunofluorescence staining protocols were used to analyze histological changes in the spleen, and the related key pathway proteins were analyzed by western blotting. Results: Ang-(1-7) decreased the expressions of the TNF-α and IL-6 pro-inflammatory cytokines and increased the expressions of the IL-4 and IL-10 anti-inflammatory cytokines. INOS and TNFα, which represented M1 macrophage polarization, were decreased by Ang-(1-7). ARG1 and CD163, which represented M2 macrophage polarization, were increased by Ang-(1-7). Both Mas receptor and ACE2 are expressed on macrophages. Furthermore, the ACE2-Ang-(1-7)-MAS axis modulated macrophage polarization by ameliorating TLR4 expression and regulating the NF-кB and MAPK pathways. In addition, splenomegaly and macrophage infiltration were observed in the spleen of the CLP-induced mouse models and macrophages in the spleen suspension of CLP models were shifted to M1 phenotype and were effectively inhibited by Ang-(1-7) via the TLR4mediated NF-кB and MAPK pathways, which could be partially rescued by A-779. Ang-(1-7) inhibited inflammatory responses in vivo and in vitro, and repressed macrophage polarization toward the M1 phenotype and promoted it toward the M2 phenotype, which provided new evidence for the anti-inflammation activity of the ACE2-Ang -(1-7)-MAS axis. Conclusion:

Monomeric CRP Aggravates Myocardial Injury After Myocardial Infarction by Polarizing the Macrophage to Pro-Inflammatory Phenotype Through JNK Signaling Pathway

“…The JNK pathway was reported to be essential for M1 macrophage polarization in HFD-fed mice, and lack of JNK decreases the expression of M1 phenotypic related genes and increased the M2 related genes in adipose tissue macrophages. 37 Furthermore, NF-κB pathway was also reported to be associated with pCRPinduced M1 macrophage polarization, 38 however, inhibition of NF-κB activation by its inhibitor had no effect on the production of mCRP-induced M1-related cytokines in our study. Therefore, our results may suggest that although mCRP was the monomeric form of CRP, they shared different signaling pathways in showing the M1 macrophage polarization bias.…”

Diminazene aceturate mitigates cardiomyopathy by interfering with renin-angiotensin system in a septic rat model

“…Another study conducted by Collins et al showed that Ang-(1-7) could affect RAW 264.7 cells by inhibiting TNF-α production in a dose-dependent manner [33]. These results were supported by several other studies [34][35][36][37], and were consistent with the decreased plasma Studies regarding the role of the RAS system in sepsis have also shown that Ang-(1-7) could attenuate the AngII-stimulated enhancement in lipid peroxidation and reduce the superoxide dismutase activity in murine hearts [38]. It was previously reported that Ang-(1-7) could stimulate protein kinase A (PKA) production via the activation of MasR, which was followed by an enhanced calcium current in the heart.…”

Angiotensin-converting enzyme 2 identifies immuno-hot tumors suggesting angiotensin-(1–7) as a sensitizer for chemotherapy and immunotherapy in breast cancer

“…Previous researches have confirmed the anti-inflammatory role of ACE2 via its enzymatic product Ang-1–7 [ 43 , 44 ]. Anti-inflammatory drugs such as COX2 inhibitors exhibits exciting effects on synergistically enhancing the efficacy of immunotherapy [ 45 ].…”