IL‐6 mediates ER expansion during hyperpolarization of alternatively activated macrophages

Abstract

Although recent evidence has shown that IL‐6 is involved in enhanced alternative activation of macrophages toward a profibrotic phenotype, the mechanisms leading to their increased secretory capacity are not fully understood. Here, we investigated the effect of IL‐6 on endoplasmic reticulum (ER) expansion and alternative activation of macrophages in vitro. An essential mediator in this ER expansion process is the IRE1 pathway, which possesses a kinase and endoribonuclease domain to cleave XBP1 into a spliced bioactive molecule. To investigate the IRE1‐XBP1 expansion pathway, IL‐4/IL‐13 and IL‐4/IL‐13/IL‐6‐mediated alternative programming of murine bone marrow‐derived and human THP1 macrophages were assessed by arginase activity in cell lysates, CD206 and arginase‐1 expression by flow cytometry, and secreted CCL18 by ELISA, respectively. Ultrastructural intracellular morphology and ER biogenesis were examined by transmission electron microscopy and immunofluorescence. Transcription profiling of 128 genes were assessed by NanoString and Pharmacological inhibition of the IRE1‐XBP1 arm was achieved using STF‐083010 and was verified by RT‐PCR. The addition of IL‐6 to the conventional alternative programming cocktail IL‐4/IL‐13 resulted in increased ER and mitochondrial expansion, profibrotic profiles and unfolded protein response‐mediated induction of molecular chaperones. IRE1‐XBP1 inhibition substantially reduced the IL‐6‐mediated hyperpolarization and normalized the above effects. In conclusion, the addition of IL‐6 enhances ER expansion and the profibrotic capacity of IL‐4/IL‐13‐mediated activation of macrophages. Therapeutic strategies targeting IL‐6 or the IRE1‐XBP1 axis may be beneficial to prevent the profibrotic capacity of macrophages.

Convolutional neural networks for multi-class brain disease detection using MRI images

“…The MR devices use powerful magnets and radiofrequency pulses instead of ionizing radiation. Furthermore, due to recent developments, it is now possible to record functional imaging of organs by using functional MR (fMR) technology (Cheng et al, 2018;Logothetis et al, 2001;Michalopoulos and Bourbakis, 2015;Saignavongs et al, 2017;. Medical imaging technologies now provide an enormous amount of data to the researchers from healthcare area to diagnose the diseases fast and accurately.…”

Bone marrow mesenchymal stem cells induce M2 microglia polarization through PDGF-AA/MANF signaling

“…ER stress-induced transcriptional upregulation of MANF is driven by an ER stress response element (ERSE)-II in the MANF promoter, and is recognized by ATF6 or XBP1s[ 26 , 27 ]. The XBP1 arm of the UPR is thought to play a critical role in enhancing the M2-like macrophage phenotype[ 28 ]. A recent study has shown that damaged retina secretes platelet-derived growth factor-AA (PDGF-AA) that signals to innate immune cells to produce MANF, which promotes macrophage M2 activation and tissue repair[ 29 ].…”

New Tools for Studying Macrophage Polarization: Application to Bacterial Infections

“…They identified nine specific distinct profiles according the agonist used, and a common transcriptomic signature, which was pertinent to isolate a polarized signature in inflammatory and infectious diseases outside of cancer [68]. Some alternative approaches to microarray such as nanostring method uses directly a panel of genes to measure their variation and may be convenient to investigate macrophage polarization [69]. Whatever the method, gene expression data must be controlled by quantitative RT-PCR, a very sensitive technic that needs low amounts of cells [70].…”