Abstract
M2-polarization and the tumoricidal to tumor-promoting transition are commonly observed with tumor-infiltrating macrophages after interplay with cancer cells or/and other stroma cells. Our previous study indicated that macrophage M2-polarization can be induced by extracellular HSP90α (eHSP90α) secreted from endothelial-to-mesenchymal transition-derived cancer-associated fibroblasts. To extend the finding, we herein validated that eHSP90α-induced M2-polarized macrophages exhibited a tumor-promoting activity and the promoted tumor tissues had significant increases in microvascular density but decreases in CD4+ T-cell level. We further investigated the signaling pathways occurring in eHSP90α-stimulated macrophages. When macrophages were exposed to eHSP90α, CD91 and toll-like receptor 4 (TLR4) functioned as the receptor/co-receptor for eHSP90α binding to recruit interleukin (IL)-1 receptor-associated kinases (IRAKs) and myeloid differentiation factor 88 (MyD88), and next elicited a canonical CD91/MyD88–IRAK1/4–IκB kinase α/β (IKKα/β)–nuclear factor-κB (NF-κB)/interferon regulatory factor 3 (IRF3) signaling pathway. Despite TLR4-MyD88 complex-associated activations of IKKα/β, NF-κB and IRF3 being well-known as involved in macrophage M1-activation, our results demonstrated that the CD91-TLR4-MyD88 complex-associated IRAK1/4−IKKα/β−NF-κB/IRF3 pathway was not only directly involved in M2-associated CD163, CD204, and IL-10 gene expressions but also required for downregulation of M1 inflammatory cytokines. Additionally, Janus kinase 2 (JAK2) and tyrosine kinase 2 (TYK2) were recruited onto MyD88 to induce the phosphorylation and activation of the transcription factor signal transducer and activator of transcription-3 (STAT-3). The JAK2/TYK2−STAT-3 signaling is known to associate with tumor promotion. In this study, the MyD88−JAK2/TYK2−STAT-3 pathway was demonstrated to contribute to eHSP90α-induced macrophage M2-polarization by regulating the expressions of M1- and M2-related genes, proangiogenic protein vascular endothelial growth factor, and phagocytosis-interfering factor Sec22b.
Highlights
Introduction conditions of the Creative CommonsMyeloid-derived cells are commonly found in tumor tissues and are associated with cancer development and progression [1]
Given that a cytokine receptor-associated Janus kinase 2 (JAK2)/tyrosine kinase 2 (TYK2)−signal transducer and activator of transcription-3 (STAT-3) signaling axis is involved in IL-4 and IL-13-induced macrophage M2-polarization, we investigated whether this signaling axis was responsible for the effects of extracellular HSP90α (eHSP90α) on macrophages
Our results showed that TNF-α, IL-1β, CD163, CD204, IL-10, and transforming growth factor-β (TGF-β) mRNA expressions changed by recombinant HSP90α (rHSP90α) in macrophages could be abrogated by the JAK2 inhibitor JAKi or/and another JAK2/TYK2 inhibitor JSI-124 (Figure 3C)
Summary
Myeloid-derived cells are commonly found in tumor tissues and are associated with cancer development and progression [1]. Accumulating evidence has demonstrated that TIMs develop a reverse role after their interactions with tumor cells, stromal cells, and factors produced within the tumor microenvironment, and promote tumor angiogenesis, growth, spreading, and immunosuppression [6,7,8,9]. This anti- to protumor transition is generally associated with M2-polarization, which is characterized by the production of anti-inflammatory factors such as interleukin (IL)-10 and transforming growth factor-β (TGF-β). Many M2 markers have been defined based on the early investigation of the macrophages treated with IL-4 and IL-13 [11], but not all of these markers can be detected in macrophages when stimulated by other M2 activators
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