Hypoxia modifies the polarization of macrophages and their inflammatory microenvironment, and inhibits malignant behavior in cancer cells

Abstract

Macrophages are a heterogeneous group of phagocytes that play critical roles in inflammation, infection and tumor growth. Macrophages respond to different environmental factors and are thereby polarized into specialized functional subsets. Although hypoxia is an important environmental factor, its impact on human macrophage polarization and subsequent modification of the inflammatory microenvironment have not been fully established. The present study aimed to elucidate the effect of hypoxia exposure on the ability of human macrophages to polarize into the classically activated (pro-inflammatory) M1, and the alternatively activated (anti-inflammatory) M2 phenotypes. The effect on the inflammatory microenvironment and the subsequent modification of A549 lung carcinoma cells was also investigated. The presented data show that hypoxia promoted macrophage polarization towards the M2 phenotype, and modified the inflammatory microenvironment by decreasing the release of proinflammatory cytokines. Modification of the microenvironment by proinflammatory M1 macrophages under hypoxia reversed the inhibition of malignant behaviors within the proinflammatory microenvironment. Furthermore, it was identified p38 signaling (a major contributor to the response to reactive oxygen species generated by hypoxic stress), but not hypoxia-induced factor, as a key regulator of macrophages under hypoxia. Taken together, the data suggest that hypoxia affects the inflammatory microenvironment by modifying the polarization of macrophages, and thus, reversing the inhibitory effects of a proinflammatory microenvironment on the malignant behaviors of several types of cancer cell.

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

“…In addition, the hypoxic tumor microenvironment can also triggers M2-polarized TAMs. 149 – 151 Once polarized, M2 TAMs secrete various growth factors and cytokines, including TGF-β, 152 , 153 interleukin-IL-10, IL-6, TNF-α, 40 , 154 , 155 IL-1β, 156 , 157 migration inhibitory factor (MIF) 158 , and chemokines such as CCL20, 159 which are all capable of promoting EMT as previously described. In addition, gemcitabine treatment results in robust infiltration of M2-polarized TAMs which secrete TNFα, TGF-β, and IL-6, leading to EMT of PDAC cells.…”

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

“…In another study, hypoxia promoted THP-1 cells polarization to M2 phenotype in HIF-1α-independent way, by decreasing IL-1β expression and increasing VEGF and CD206 expression [272]. In patients with glioma, IHC analysis revealed the positive correlation between HIF-1α expression, periostin (POSTN) expression, and the infiltration of TAMs (CD11b+) and M2 type TAMs (CD206+) in tumor sections.…”

Macrophage Polarization and Osteoporosis: A Review

“…Thus, macrophage populations are in constant flux, quickly sensing and reacting to changes in the microenvironment to maintain homeostatic balance. Aside from cytokines present in the microenvironment, other factors that influence macrophage phenotype include: (1) Metabolite concentrations—M1 macrophages produce high succinate levels which increase IL-1β and promote inflammation via the stabilization of hypoxia inducible factor 1 alpha (HIF1α) [ 39 ]; (2) Oxygen concentrations—hypoxic conditions favor M2 macrophage polarization and resolution of inflammation [ 40 ]; (3) Acidification—increased lactic acid production in tumors has shown to induce M2 polarization [ 41 ]; (4) Tissue osmolality—macrophages sense hypertonic conditions and upregulate production of caspase-1 and IL-1β, resulting in an M1 like phenotype [ 42 ].…”