Extracellular HSP90α Induces MyD88-IRAK Complex-Associated IKKα/β−NF-κB/IRF3 and JAK2/TYK2−STAT-3 Signaling in Macrophages for Tumor-Promoting M2-Polarization

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.

HSP90α induces immunosuppressive myeloid cells in melanoma via TLR4 signaling

“…It is known that HSP90α interacts also with LRP1. 21 38 Zou et al 19 found that two evolutionarily conserved lysine residues, Lys-270 and Lys-277, of HSP90α contained in the subfragments F-5 and F-6 were responsible for the binding of HSP90α to LRP1 on human cancer cells. In contrast, we demonstrated that these subfragments failed to upregulate PD-L1 on human monocytes.…”

“…It has been recently published that rHSP90α can trigger both LRP1 and TLR4 on THP1-derived macrophages, RAW264.7 macrophage cell line and bone marrow-derived macrophages, resulting in the upregulation of CD163, CD204, IL-10 and downregulation of TNF-α, IL-1β as well as in the depletion of CD4 T cells from the pancreatic tumor. 21 It is possible that rHSP90α in myeloid cells forms a complex with TLR4 and LRP1, in which TLR4 plays a pivotal role. Moreover, HSP90α and HSP90β were reported to be expressed on the surface of monocytes and macrophages and to participate in cytokine response to TLR4 ligands by building a signaling complex with TLR4.…”

Targeting extracellular Hsp90: A unique frontier against cancer

“…Treatment with Hsp90 inhibitor selectively interfered with the tumorigenic MIF that assisted in promoting angiogenic gene expression in tumor cells (Klemke et al, 2021). Extracellular Hsp90 also induced M2-polarized macrophages to demonstrate tumorpromoting activities including upregulation of M2 markers, phagocytosis repressors, and angiogenesis activators mediated through several signaling pathways (Fan et al, 2022). Extracellular Hsp90 is also involved in lymphangiogenesis.…”

Osteopathy in Complex Lymphatic Anomalies

“…Additionally, VEGF-C treatment is known to stimulate OC in a similar manner as M-CSF [ 107 ]. Macrophages (OC progenitors) and MSC are also known to secrete various VEGF factors, including VEGF-C [ 8 , 108 ]. These VEGF-C sources might readily further stimulate lymphatic invasion and trigger bone resorption.…”