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CpG Oligodeoxynucleotides Attenuate OVA-Induced Allergic Airway Inflammation via Suppressing JNK-Mediated Endoplasmic
Hai-Yun Zhang1,2,3, Qiu-Meng Xie1,2,3, Cui-Cui Zhao1,2,3
1Anhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China.
Purpose:
CpG-ODN has been found to attenuate allergic airway inflammation in our previous study. Here, we aimed to further investigate whether CpG-ODN exerts such effect via regulating endoplasmic reticulum (ER) stress and revealed the underlying mechanism.
Methods:
Five-week-old C57BL/6 mice were randomly grouped and treated with or without CpG-ODN or/and SP600125. Meantime, RAW264.7 cells were used to investigate the effect of CpG-ODN on OVA-induced ER stress in vitro. The cellularity of bronchoalveolar lavage fluid (BALF) was classified and counted after Wright-Giemsa staining. HE and PAS staining methods were applied to analyze airway inflammation. The protein levels of IL-4, IL-5, IL-13, p-JNK, JNK, CHOP, XBP1, ATF6α and GRP78 in lung tissues were detected by Western blotting. Correspondingly, the ER stress markers were detected by Western blotting and immunofluorescence in RAW264.7 cells.
Results:
In OVA-induced allergic airway inflammation, CpG-ODN significantly suppressed inflammatory cells infiltration, goblet cell hyperplasia and the protein expression of Th2 cytokines. Moreover, OVA exposure strongly increased the activation of ER stress with higher protein expressions of CHOP, XBP1, ATF6α and GRP78. However, these OVA-induced increase of ER stress markers were markedly suppressed by CpG-ODN treatment. In addition, exposure to OVA significantly increased the phosphorylation of JNK, which was significantly reduced by CpG-ODN treatment. Remarkably, single treatment of SP600125, an antagonist of JNK, functioned similarly as CpG-ODN in mitigating allergic airway inflammation and suppressing OVA-induced activation of ER stress; however, no significant synergistic effect was evidenced by combined treatment of SP600125 and CpG-ODN. Furthermore, in OVA-stimulated RAW264.7 cells, we also found that OVA stimulation increased the expressions of ER stress markers, and CpG-ODN significantly reduced their expression levels via suppressing the phosphorylation of JNK.
Conclusion:
These results indicated that CpG-ODN mitigates allergic airway inflammation via suppressing the activation of JNK-medicated ER stress.
Insights
CpG-ODN reduces allergic airway inflammation by inhibiting JNK-mediated endoplasmic reticulum (ER) stress. This study reveals the mechanism by which CpG-ODN alleviates airway inflammation and ER stress.
Area of Science:
- Immunology
- Cell Biology
- Respiratory Medicine
Background:
- CpG-ODN has previously shown potential in reducing allergic airway inflammation.
- Endoplasmic reticulum (ER) stress is implicated in the pathogenesis of allergic airway inflammation.
- The precise mechanism by which CpG-ODN exerts its anti-inflammatory effects requires further elucidation.
Purpose of the Study:
- To investigate if CpG-ODN attenuates allergic airway inflammation by regulating ER stress.
- To elucidate the underlying molecular mechanisms, specifically the role of JNK signaling.
Main Methods:
- Utilized a mouse model of ovalbumin (OVA)-induced allergic airway inflammation.
- Administered CpG-ODN and SP600125 (JNK inhibitor) to assess their effects.
- Analyzed bronchoalveolar lavage fluid cellularity and performed histological staining (HE, PAS) for airway inflammation.
- Quantified protein levels of inflammatory cytokines (IL-4, IL-5, IL-13) and ER stress markers (CHOP, XBP1, ATF6α, GRP78) via Western blotting.
- Investigated CpG-ODN's effect on OVA-induced ER stress in RAW264.7 cells in vitro.
Main Results:
- CpG-ODN significantly suppressed inflammatory cell infiltration, goblet cell hyperplasia, and Th2 cytokine expression in OVA-induced allergic airway inflammation.
- OVA exposure increased ER stress markers (CHOP, XBP1, ATF6α, GRP78) and JNK phosphorylation, which were reduced by CpG-ODN.
- SP600125 (JNK inhibitor) mimicked CpG-ODN's effects, but no synergistic effect was observed with combined treatment.
- In vitro studies confirmed that CpG-ODN reduced OVA-induced ER stress markers by suppressing JNK phosphorylation in RAW264.7 cells.
Conclusions:
- CpG-ODN mitigates allergic airway inflammation by suppressing JNK-mediated ER stress.
- The findings highlight a novel mechanism involving the JNK/ER stress pathway in CpG-ODN's therapeutic effects.
- CpG-ODN represents a potential therapeutic agent for allergic airway inflammation targeting the JNK-ER stress axis.
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