quaking deficiency amplifies inflammation in experimental endotoxemia via the aryl hydrocarbon receptor/signal transducer and activator of transcription 1–nf-κb pathway

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ID: 149886
2017
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Abstract
Macrophages, characterized by considerable diversity and plasticity, play a crucial role in a broad spectrum of biological processes, including inflammation. However, the molecular mechanisms underlying the diverse phenotypes of macrophages are not well defined. Here, we show that the RNA-binding protein, quaking (QKI), dynamically modulates macrophage polarization states. After lipopolysaccharide (LPS) stimulation, QKI-silenced RAW 264.7 cells displayed a pro-inflammatory M1 phenotype characterized by increased expression of iNOS, TNF-α, and IL-6 and decreased expression of anti-inflammatory factors, such as IL-10, found in inflammatory zone (Fizz1), and chitinase-like 3 (Chil3 or Ym1). By contrast, QKI5 overexpression led to a suppressive phenotype resembling M2 macrophages, even under M1 differentiation conditions. Moreover, myeloid-specific QKI-deficient mice tended to be more susceptible to LPS-induced endotoxic shock, while the exogenous transfer of macrophages overexpressing QKI5 exerted a significant improving effect. This improvement corresponded to a higher proportion of M2 macrophages, in line with elevated levels of IL-10, and a decrease in levels of pro-inflammatory mediators, such as IL-6, TNF-α, and IL-1β. Further mechanistic studies disclosed that QKI was a potent inhibitor of the nuclear factor-kappa B (NF-κB) pathway, suppressing p65 expression and phosphorylation. Strikingly, reduced expression of the aryl hydrocarbon receptor (Ahr) and reduced phosphorylation of signal transducer and activator of transcription 1 in QKI-deficient cells failed to restrain the transcriptional activity of NF-κB and NRL pyrin domain containing 3 (NLRP3) activation, while restoring QKI expression skewed the above M1-like response toward an anti-inflammatory M2 state. Taken together, these findings suggest a role for QKI in restraining overt innate immune responses by regulating the Ahr/STAT1–NF-κB pathway.
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wang2017frontiersquaking Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Li Wang;Dong-Sheng Zhai;Ban-Jun Ruan;Cheng-Ming Xu;Zi-Chen Ye;Huan-Yu Lu;Ying-Hao Jiang;Zhen-Yu Wang;An Xiang;Yuan Yang;Jian-Lin Yuan;Zi-Fan Lu
Journal sudebno-meditsinskaia ekspertiza
Year 2017
DOI
10.3389/fimmu.2017.01754
URL
http://journal.frontiersin.org/article/10.3389/fimmu.2017.01754/full
Keywords
aryl hydrocarbon receptor endotoxemia macrophage polarization allergy

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