Regulation of γδT17 cells by <i>Mycobacterium vaccae</i> through interference with Notch/Jagged1 signaling pathway

The objective of this study was to investigate the effect of Mycobacterium vaccae on Jagged 1 and gamma delta T17 (γδT17) cells in asthmatic mice. An asthma mouse model was established through immunization with ovalbumin (OVA). Gamma-secretase inhibitor (DAPT) was used to block the Notch signaling pathway. M. vaccae was used to treat asthma, and related indicators were measured. Blocking Notch signaling inhibited the production of γδT17 cells and secretion of cytokine interleukin (IL)-17, which was accompanied by a decrease in Jagged1 mRNA and protein expression in the treated asthma group compared with the untreated asthma group. Similarly, treatment with M. vaccae inhibited Jagged1 expression and γδT17 cell production, which was associated with decreased airway inflammation and reactivity. The Notch signaling pathway may play a role in the pathogenesis of asthma through the induction of Jagged1 receptor. On the other hand, the inhibitory effect of M. vaccae on Jagged1 receptor in γδT17 cells could be used for the prevention and treatment of asthma.

Asthma; Mycobacterium vaccae; Jagged1 receptor; γδT17; Notch signaling

Authorship

Yi En Yao

Department of Respiratory Medicine, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, ChinaFirst Affiliated Hospital of Guangxi Medical UniversityChinaNanning, Guangxi, ChinaDepartment of Respiratory Medicine, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China

https://orcid.org/0000-0003-4764-7859

Jing Hong Zhang

Department of Internal Medicine, Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi, ChinaDepartment of Internal Medicine, Affiliated Tumor Hospital, Guangxi Medical UniversityChinaNanning, Guangxi, ChinaDepartment of Internal Medicine, Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi, China

https://orcid.org/0000-0002-2797-7730

Xiao Ju Chen

Department of Critical Care, First People's Hospital of Yulin City, Nanning, Guangxi, ChinaFirst People's Hospital of Yulin CityChinaNanning, Guangxi, ChinaDepartment of Critical Care, First People's Hospital of Yulin City, Nanning, Guangxi, China

https://orcid.org/0000-0002-3579-0247

Jian Lin Huang

https://orcid.org/0000-0001-6397-7773

Qi Xiang Sun

https://orcid.org/0000-0002-4661-4716

Wei Wei Liu

Department of Emergency Medicine, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, ChinaFirst Affiliated Hospital of Guangxi Medical UniversityChinaNanning, Guangxi, ChinaDepartment of Emergency Medicine, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China

https://orcid.org/0000-0001-6257-0656

Huan Zeng

The Second Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, ChinaSecond Affiliated Hospital, Guangxi Medical UniversityChinaNanning, Guangxi, ChinaThe Second Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China

https://orcid.org/0000-0002-7890-4072

Chao Qian Li Correspondence: Chao Qian Li: <lichaoqiangood@163.com>

https://orcid.org/0000-0002-0916-3661

Correspondence: Chao Qian Li: <lichaoqiangood@163.com>

SCIMAGO INSTITUTIONS RANKINGS

Figures

Figures (7)

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Figure 1
Effects of inhaled inactivated Mycobacterium vaccae on airway hyperresponsiveness with methacholine (Mch) treatment. Airway reactivity was measured using specific airway resistance (sRaw). Ovalbumin (OVA) challenge significantly increased sRaw in all 4 methacholine doses with the maximum increase achieved in the dose 50 mg/mL. Data are reported as mean±SE relative percentage to the control group (n=8). *P<0.05, ^$$P<0.01, **P<0.01 vs control group; ^#P<0.05, ^&P<0.05, ^&&P<0.01, ^##P<0.01 vs asthma group (ANOVA).

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Figure 2
Lung histopathology was detected using hematoxylin and eosin (HE) and Periodic acid-Schiff (PAS) staining. Effects of inactivated Mycobacterium vaccae on ovalbumin (OVA)-induced airway inflammation. Histological examination of normal control group (a), asthma group (b), gamma-secretase inhibitor (DAPT + OVA group (c), M. vaccae + OVA group (d), OVA + M. vaccae group (e). HE staining: original magnification ×400, scale bar=50 μm; PAS staining: original magnification ×200, scale bar=100 μm.

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Figure 3
Expression of Jagged1 using immunohistochemical and immunofluorescence stains (A) in mice in control group (a), asthma group (b), gamma-secretase inhibitor (DAPT) + ovalbumin (OVA) group (c), Mycobacterium vaccae + OVA group (d), OVA + M. vaccae group (e), and its quantification (B and C). Data are reported as mean±SE relative percentage to the control group (n=8). ^##P<0.01 vs control; **P <0.01 vs asthma group (ANVOA). Original magnification x400, scale bar=50 μm.

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Figure 4
The mRNA expression of Jagged1 in lung tissues was determined using real-time PCR. Data are reported as mean±SE relative percentage to the control group (n=8). *P<0.05 vs control; ^#P<0.05 vs asthma group (ANOVA). OVA: ovalbumin; DAPT: gamma-secretase inhibitor.

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Figure 5
Interleukin (IL)-17A concentrations in serum by ELISA using specific cytokine detection kits. Data are reported as mean±SE relative percentage to the control group (n=8). **P<0.01 vs control; ^#P<0.05, ^##P<0.01 vs asthma group (ANOVA). OVA: ovalbumin; DAPT: gamma-secretase inhibitor.

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Figure 6
Correlation analysis between Jagged1 and γδT17 cells in lung tissues. A and B, The ratio of IL-17+γδT+ cells to T cells was measured in each group. C, The percentage of IL-17+γδT+ cells and the Jagged1 mRNA expression in lung tissues were positively correlated (r=0.46, P<0.05). Data are reported as mean±SE relative percentage to the control group (n=8). **P<0.01 vs control; *P<0.05, ^##P<0.01 vs asthma group (ANOVA). OVA: ovalbumin; DAPT: gamma-secretase inhibitor.

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Figure 7
Mycobacterium vaccae spleens from ovalbumin (OVA)-treated mice were compared to the control, asthma, gamma-secretase inhibitor (DAPT)+OVA, M. vaccae + OVA, and OVA + M. vaccae groups to determine the percentage of γδT17 cells among the CD3+ T cells by flow cytometry. Data are reported as mean±SE relative percentage to the control group (n=8). **P<0.01 vs control; *P<0.05, ^##P<0.01 vs asthma group (ANOVA).

Figure 1 Effects of inhaled inactivated Mycobacterium vaccae on airway hyperresponsiveness with methacholine (Mch) treatment. Airway reactivity was measured using specific airway resistance (sRaw). Ovalbumin (OVA) challenge significantly increased sRaw in all 4 methacholine doses with the maximum increase achieved in the dose 50 mg/mL. Data are reported as mean±SE relative percentage to the control group (n=8). *P<0.05, ^$$P<0.01, **P<0.01 vs control group; ^#P<0.05, ^&P<0.05, ^&&P<0.01, ^##P<0.01 vs asthma group (ANOVA).

Figure 2 Lung histopathology was detected using hematoxylin and eosin (HE) and Periodic acid-Schiff (PAS) staining. Effects of inactivated Mycobacterium vaccae on ovalbumin (OVA)-induced airway inflammation. Histological examination of normal control group (a), asthma group (b), gamma-secretase inhibitor (DAPT + OVA group (c), M. vaccae + OVA group (d), OVA + M. vaccae group (e). HE staining: original magnification ×400, scale bar=50 μm; PAS staining: original magnification ×200, scale bar=100 μm.

Figure 3 Expression of Jagged1 using immunohistochemical and immunofluorescence stains (A) in mice in control group (a), asthma group (b), gamma-secretase inhibitor (DAPT) + ovalbumin (OVA) group (c), Mycobacterium vaccae + OVA group (d), OVA + M. vaccae group (e), and its quantification (B and C). Data are reported as mean±SE relative percentage to the control group (n=8). ^##P<0.01 vs control; **P <0.01 vs asthma group (ANVOA). Original magnification x400, scale bar=50 μm.

Figure 4 The mRNA expression of Jagged1 in lung tissues was determined using real-time PCR. Data are reported as mean±SE relative percentage to the control group (n=8). *P<0.05 vs control; ^#P<0.05 vs asthma group (ANOVA). OVA: ovalbumin; DAPT: gamma-secretase inhibitor.

Figure 5 Interleukin (IL)-17A concentrations in serum by ELISA using specific cytokine detection kits. Data are reported as mean±SE relative percentage to the control group (n=8). **P<0.01 vs control; ^#P<0.05, ^##P<0.01 vs asthma group (ANOVA). OVA: ovalbumin; DAPT: gamma-secretase inhibitor.

Figure 6 Correlation analysis between Jagged1 and γδT17 cells in lung tissues. A and B, The ratio of IL-17+γδT+ cells to T cells was measured in each group. C, The percentage of IL-17+γδT+ cells and the Jagged1 mRNA expression in lung tissues were positively correlated (r=0.46, P<0.05). Data are reported as mean±SE relative percentage to the control group (n=8). **P<0.01 vs control; *P<0.05, ^##P<0.01 vs asthma group (ANOVA). OVA: ovalbumin; DAPT: gamma-secretase inhibitor.

Figure 7 Mycobacterium vaccae spleens from ovalbumin (OVA)-treated mice were compared to the control, asthma, gamma-secretase inhibitor (DAPT)+OVA, M. vaccae + OVA, and OVA + M. vaccae groups to determine the percentage of γδT17 cells among the CD3+ T cells by flow cytometry. Data are reported as mean±SE relative percentage to the control group (n=8). **P<0.01 vs control; *P<0.05, ^##P<0.01 vs asthma group (ANOVA).

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Regulation of γδT17 cells by <i>Mycobacterium vaccae</i> through interference with Notch/Jagged1 signaling pathway

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[1] Correspondence: Chao Qian Li: <lichaoqiangood@163.com>