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HSPA12B Secreted by Tumor-Associated Endothelial Cells Might Induce M2 Polarization of Macrophages via Activating PI3K/Akt/mTOR Signaling.

ABSTRACT: Purpose:The intratumoral microenvironment of head and neck squamous cell carcinoma (HNSC) is highly immunosuppressive. In this study, we explored the potential functional role of HSPA12B secreted by tumor-associated endothelial cells (TECs) in M2 polarization of macrophages. Materials and Methods:Bulk-seq data from TCGA-HNSC and single-cell RNA-seq data from GSE103322 (with over 5000 cells from 18 primary HNSC cases) were used for bioinformatic analysis. RAW264.7 cell line was used for in vitro studies. Results:TECs in HNSC had significantly higher expression and secretion of HSPA12B, compared to normal human umbilical vein endothelial cells (HUVECs). Exogenous HSPA12B treatment increased the expression of M2 macrophage marker CD163 and CD206 on RAW264.7 cells in a dose-dependent manner but had no significant influence on CD86, an M1 macrophage marker. OLR1, a known receptor of HSP70 proteins, was specifically expressed in tumor-associated macrophages (TAMs) in HNSC. OLR1 knockdown significantly impaired HSPA12B uptake by RAW264.7 cells and weakened HSPA12B-induced CD163 and CD206 upregulation. HSPA12B treatment increased the expression of p-PI3K, p-Akt and p-mTOR in a dose-dependent manner in RAW264.7 cells. OLR1 inhibition and LY294002 treatment significantly weakened the effects HSPA12B on activating the PI3K/Akt/mTOR signaling and M2 marker expression. Conclusion:Based on these findings, we speculated that aberrantly expressed and secreted HSPA12B by TECs could be taken by macrophages partly via OLR1, leading to subsequent activation of the PI3K/Akt/mTOR signaling pathway and elevated expression of M2 markers. This mechanism shows a novel cross-talk between TECs and TAMs, which contributes to the intratumoral immunosuppressive microenvironment.

SUBMITTER: Zhou J

PROVIDER: S-EPMC7494226 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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HSPA12B Secreted by Tumor-Associated Endothelial Cells Might Induce M2 Polarization of Macrophages via Activating PI3K/Akt/mTOR Signaling.

Zhou Jingjie J Zhang Aiping A Fan Liang L

OncoTargets and therapy 20200911

<h4>Purpose</h4>The intratumoral microenvironment of head and neck squamous cell carcinoma (HNSC) is highly immunosuppressive. In this study, we explored the potential functional role of HSPA12B secreted by tumor-associated endothelial cells (TECs) in M2 polarization of macrophages.<h4>Materials and methods</h4>Bulk-seq data from TCGA-HNSC and single-cell RNA-seq data from GSE103322 (with over 5000 cells from 18 primary HNSC cases) were used for bioinformatic analysis. RAW264.7 cell line was use ...[more]

PMID: 32982299

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Project description:BackgroundLarvae of Echinococcus granulosus (sensu lato) dwell in host organs for a long time but elicit only a mild inflammatory response, which indicates that the resolution of host inflammation is necessary for parasite survival. The recruitment of alternatively activated macrophages (AAMs) has been observed in a variety of helminth infections, and emerging evidence indicates that AAMs are critical for the resolution of inflammation. However, whether AAMs can be induced by E. granulosus (s.l.) infection or thioredoxin peroxidase (TPx), one of the important molecules secreted by the parasite, remains unclear.MethodsThe activation status of peritoneal macrophages (PMs) derived from mice infected with E. granulosus (sensu stricto) was analyzed by evaluating the expression of phenotypic markers. PMs were then treated in vivo and in vitro with recombinant EgTPx (rEgTPx) and its variant (rvEgTPx) in combination with parasite excretory-secretory (ES) products, and the resulting activation of the PMs was evaluated by flow cytometry and real-time PCR. The phosphorylation levels of various molecules in the PI3K/AKT/mTOR pathway after parasite infection and antigen stimulation were also detected.ResultsThe expression of AAM-related genes in PMs was preferentially induced after E. granulosus (s.s.) infection, and phenotypic differences in cell morphology were detected between PMs isolated from E. granulosus (s.s.)-infected mice and control mice. The administration of parasite ES products or rEgTPx induced the recruitment of AAMs to the peritoneum and a notable skewing of the ratio of PM subsets, and these effects are consistent with those obtained after E. granulosus (s.s.) infection. ES products or rEgTPx also induced PMs toward an AAM phenotype in vitro. Interestingly, this immunomodulatory property of rEgTPx was dependent on its antioxidant activity. In addition, the PI3K/AKT/mTOR pathway was activated after parasite infection and antigen stimulation, and the activation of this pathway was suppressed by pre-treatment with an AKT/mTOR inhibitor.ConclusionsThis study demonstrates that E. granulosus (s.s.) infection and ES products, including EgTPx, can induce PM recruitment and alternative activation, at least in part, via the PI3K/AKT/mTOR pathway. These results suggest that EgTPx-induced AAMs might play a key role in the resolution of inflammation and thereby favour the establishment of hydatid cysts in the host.

Dataset Information

HSPA12B Secreted by Tumor-Associated Endothelial Cells Might Induce M2 Polarization of Macrophages via Activating PI3K/Akt/mTOR Signaling.

Publications

HSPA12B Secreted by Tumor-Associated Endothelial Cells Might Induce M2 Polarization of Macrophages via Activating PI3K/Akt/mTOR Signaling.

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