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IL ‐6 mediates ER expansion during hyperpolarization of alternatively activated macrophages
Author(s) -
Ayaub Ehab A,
Tandon Karun,
Padwal Manreet,
Imani Jewel,
Patel Hemisha,
Dubey Anisha,
Mekhael Olivia,
Upagupta Chandak,
Ayoub Anmar,
DvorkinGheva Anna,
Murphy James,
Kolb Philipp S,
Lhotak Sarka,
Dickhout Jeffrey G,
Austin Rick C,
Kolb Martin R J,
Richards Carl D,
Ask Kjetil
Publication year - 2019
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1111/imcb.12212
Subject(s) - microbiology and biotechnology , unfolded protein response , endoplasmic reticulum , chemistry , arginase , signal transduction , biology , biochemistry , amino acid , arginine
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 IRE 1 pathway, which possesses a kinase and endoribonuclease domain to cleave XBP 1 into a spliced bioactive molecule. To investigate the IRE 1‐ XBP 1 expansion pathway, IL ‐4/ IL ‐13 and IL ‐4/ IL ‐13/ IL ‐6‐mediated alternative programming of murine bone marrow‐derived and human THP 1 macrophages were assessed by arginase activity in cell lysates, CD 206 and arginase‐1 expression by flow cytometry, and secreted CCL 18 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 IRE 1‐ XBP 1 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. IRE 1‐ XBP 1 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 IRE 1‐ XBP 1 axis may be beneficial to prevent the profibrotic capacity of macrophages.