Macrophage transcriptome modification induced by hypoxia and lactate

Zhao,Yang; Zhao,Bin; Wang,Xin; Guan,Ge; Xin,Yang; Sun,Yan  Dong; Wang,Jian  Hong; Guo,Yuan; Zang,Yun  Jin

doi:10.3892/etm.2019.8164

Macrophage transcriptome modification induced by hypoxia and lactate

Authors:
- Yang Zhao
- Bin Zhao
- Xin Wang
- Ge Guan
- Yang Xin
- Yan Dong Sun
- Jian Hong Wang
- Yuan Guo
- Yun Jin Zang
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Affiliations: Department of Transplantation, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China, Department of Breast Disease, Peking Union Medical College Hospital, Peking Union Medical College, Beijing 100730, P.R. China
Published online on: November 4, 2019 https://doi.org/10.3892/etm.2019.8164
Pages: 4811-4819
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The production of lactate under hypoxic conditions or by cancer cells was reported to promote the M2 polarization of tumor‑associated macrophages. However, the exact effect of lactate on macrophages, particularly under hypoxic conditions, has remained largely elusive. In the present study, an in‑depth bioinformatics analysis of previously published transcriptome data of macrophages was performed. A total of 6, 101 and 764 upregulated genes were identified in the lactate, hypoxia and hypoxia‑lactate groups, respectively, whereas 4, 41 and 588 genes were downregulated in the same respective groups. Furthermore, differentially expressed genes (DEGs) of the hypoxia and hypoxia‑lactate groups were significantly enriched in the hypoxia‑inducible factor 1 (HIF‑1) signaling pathway and the Hedgehog pathway. Upregulation of the mTOR and Hedgehog pathways in the hypoxia‑lactate group was identified by gene set enrichment analysis. Furthermore, a set of HIF‑1 pathway‑associated genes was identified to be positively correlated with hypoxia using weighted gene co‑expression network analysis. Lactate was indicated to inhibit the cell cycle in a hypoxia‑independent manner. The DEGs of the hypoxia and hypoxia‑lactate groups, including C‑C motif chemokine receptor type 1 and 5, were enriched in the cytokine‑cytokine receptor interaction pathway. In conclusion, under normoxic conditions, lactate exerted a weak effect on macrophages, while the combination of lactate and hypoxia markedly promoted the M2‑polarization of macrophages via the HIF‑1, Hedgehog and mTOR pathways. Lactate and hypoxia may also contribute to the formation of the spatial structure of tumor niches by inhibiting the proliferation of resident macrophages and by regulating the recruitment of peripheral macrophages.

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