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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.

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