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Short-chain fatty acids ameliorate allergic airway inflammation via sequential induction of PMN-MDSCs and Treg cells

Huang, Min-Ting, Chiu, Chiao-Juno, Tsai, Ching-Yi, Lee, Yue-Ru, Liu, Wei-Liang, Chuang, Hsiao-Li, Huang, Miao-Tzu·2023·Journal of Allergy and Clinical Immunology: Global
DOI 10.1016/j.jacig.2023.100163PMC PMC10509984
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Fig 1 Alleviation of allergen-induced acute airway inflammation by SCFAs. A, Schematic diagram depicting the experimental protocol for establishing the OVA-induced murine allergic airway inflammation model and SCFA supplementation, as detailed in the Methods section. B, Serum levels of OVA-specific IgE antibody examined at 1 week after the second intraperitoneal (i.p.) OVA sensitization. C, IL-5 expression in BALF and culture supernatants of OVA-restimulated splenocytes. D, Microphotographs showed hematoxylin and eosin–stained lung tissues after aerosol OVA challenge. E, Total and differential BALF leukocyte counts enumerated by Giemsa- and May-Grünwald–stained cytospins. F, Airway hyperresponsiveness (AHR) presented as airway resistance in response to escalating concentrations of methacholine. n = 7 mice/group. Data shown represent 1 of 4 independent experiments. ∗ and #, OVA-treated group compared with the PBS- and SCFA-treated groups, respectively. B, C, and E, Each symbol refers to 1 independently treated mouse. P values were determined by using an unpaired t test. ∗∗P < .01; ∗∗∗P < .001; ###P < .001. Eos, Eosinophil; i.h., inhalation; Lym, lymphocyte; Mo, monocyte; Neu, neutrophil; Pos Ctrl, positive control.
Fig 1 Alleviation of allergen-induced acute airway inflammation by SCFAs. A, Schematic diagram depicting the experimental protocol for establishing the OVA-induced murine allergic airway inflammation model and SCFA supplementation, as detailed in the Methods section. B, Serum levels of OVA-specific IgE antibody examined at 1 week after the second intraperitoneal (i.p.) OVA sensitization. C, IL-5 expression in BALF and culture supernatants of OVA-restimulated splenocytes. D, Microphotographs showed hematoxylin and eosin–stained lung tissues after aerosol OVA challenge. E, Total and differential BALF leukocyte counts enumerated by Giemsa- and May-Grünwald–stained cytospins. F, Airway hyperresponsiveness (AHR) presented as airway resistance in response to escalating concentrations of methacholine. n = 7 mice/group. Data shown represent 1 of 4 independent experiments. ∗ and #, OVA-treated group compared with the PBS- and SCFA-treated groups, respectively. B, C, and E, Each symbol refers to 1 independently treated mouse. P values were determined by using an unpaired t test. ∗∗P < .01; ∗∗∗P < .001; ###P < .001. Eos, Eosinophil; i.h., inhalation; Lym, lymphocyte; Mo, monocyte; Neu, neutrophil; Pos Ctrl, positive control.CC BY-NC-ND · PubMed Central
Fig 2 SCFAs dampened DC Notch signaling and induced Treg cell and MDSC differentiation. Three-week-old female BALB/c mice were given drinking water containing a cocktail of SCFAs for 2 weeks before initiation of OVA sensitization and challenges as depicted in Fig 1. A. A, Expression of Notch ligands Jag1 and DLL4 by BM-derived DCs after SCFA treatment (upper) or BALF DCs infiltrating into the lung during allergic airway inflammation (bottom). Populations of Treg cells (B) and MDSCs (C) in various tissues, including BM, peripheral blood (PB), spleen, lungs, and BALF, were analyzed by FACS. A-C, Each symbol refers to 1 independently treated mouse. A, (top) Data shown represent 1 of 3 independent in vitro culture each performed in triplicate. P values were determined by using an unpaired t test. ∗∗P < .01; ∗∗∗ P < .001.
Fig 2 SCFAs dampened DC Notch signaling and induced Treg cell and MDSC differentiation. Three-week-old female BALB/c mice were given drinking water containing a cocktail of SCFAs for 2 weeks before initiation of OVA sensitization and challenges as depicted in Fig 1. A. A, Expression of Notch ligands Jag1 and DLL4 by BM-derived DCs after SCFA treatment (upper) or BALF DCs infiltrating into the lung during allergic airway inflammation (bottom). Populations of Treg cells (B) and MDSCs (C) in various tissues, including BM, peripheral blood (PB), spleen, lungs, and BALF, were analyzed by FACS. A-C, Each symbol refers to 1 independently treated mouse. A, (top) Data shown represent 1 of 3 independent in vitro culture each performed in triplicate. P values were determined by using an unpaired t test. ∗∗P < .01; ∗∗∗ P < .001.CC BY-NC-ND · PubMed Central
Fig 3 MDSC depletion aggravated allergic airway inflammation. A, Diagram depicting the experiment protocol of MDSC depletion along the course of OVA-induced airway inflammation. Briefly, the indicated mice were given GR1-depleting antibody twice a week commencing 1 week before OVA sensitization and continued until aerosol OVA challenge. B, Serum levels of OVA-specific IgE antibody were measured by ELISA, and leukocyte subpopulations in BALF were enumerated by Giemsa- and May-Grünwald–stained cytospins. C, Cytokine expression in BALF and culture supernatants of OVA-restimulated splenocytes were measured by ELISA. Each dot refers to 1 independently treated mouse. P values were determined by using an unpaired t test. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. i.h., Inhalation; i.p., intraperitoneal; i.v., intravenous.
Fig 3 MDSC depletion aggravated allergic airway inflammation. A, Diagram depicting the experiment protocol of MDSC depletion along the course of OVA-induced airway inflammation. Briefly, the indicated mice were given GR1-depleting antibody twice a week commencing 1 week before OVA sensitization and continued until aerosol OVA challenge. B, Serum levels of OVA-specific IgE antibody were measured by ELISA, and leukocyte subpopulations in BALF were enumerated by Giemsa- and May-Grünwald–stained cytospins. C, Cytokine expression in BALF and culture supernatants of OVA-restimulated splenocytes were measured by ELISA. Each dot refers to 1 independently treated mouse. P values were determined by using an unpaired t test. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. i.h., Inhalation; i.p., intraperitoneal; i.v., intravenous.CC BY-NC-ND · PubMed Central
Fig 4 Alleviation of airway inflammation by SCFAs was abrogated after MDSC depletion. A, Diagram showing the experiment protocol of MDSC depletion and SCFA supplementation in OVA-induced murine allergic airway inflammation model. B, Microphotographs showing hematoxylin and eosin–stained lung sections taken at 1 day after OVA challenge. C, Total and differential leukocyte counts in the BALF were enumerated by cytospins. D, IL-5 expression in BALF and supernatants of OVA-restimulated splenocytes was examined by ELISA. E, Airway hyperresponsiveness (AHR) in response to escalating concentrations of methacholine. n = 7 mice/group. Data shown represent 1 of 2 independent experiments. ∗Positive control and anti-GR1 groups compared with the SCFA group; #Positive control and anti-GR1 groups compared with the PBS group. C and D, Each symbol refers to 1 independently treated mouse. P values were determined by using an unpaired t test or 1-way ANOVA. ∗ P < .05; #P < .05; ∗∗ P < .01; ##P < .01; ∗∗∗P < .001. Eos, Eosinophil; Lym, lymphocyte; Mo, monocyte; Neu, neutrophil; Pos Ctrl, positive control.
Fig 4 Alleviation of airway inflammation by SCFAs was abrogated after MDSC depletion. A, Diagram showing the experiment protocol of MDSC depletion and SCFA supplementation in OVA-induced murine allergic airway inflammation model. B, Microphotographs showing hematoxylin and eosin–stained lung sections taken at 1 day after OVA challenge. C, Total and differential leukocyte counts in the BALF were enumerated by cytospins. D, IL-5 expression in BALF and supernatants of OVA-restimulated splenocytes was examined by ELISA. E, Airway hyperresponsiveness (AHR) in response to escalating concentrations of methacholine. n = 7 mice/group. Data shown represent 1 of 2 independent experiments. ∗Positive control and anti-GR1 groups compared with the SCFA group; #Positive control and anti-GR1 groups compared with the PBS group. C and D, Each symbol refers to 1 independently treated mouse. P values were determined by using an unpaired t test or 1-way ANOVA. ∗ P < .05; #P < .05; ∗∗ P < .01; ##P < .01; ∗∗∗P < .001. Eos, Eosinophil; Lym, lymphocyte; Mo, monocyte; Neu, neutrophil; Pos Ctrl, positive control.CC BY-NC-ND · PubMed Central
Fig 5 SCFAs enhanced Treg cell differentiaion. Female BALB/c mice were given SCFA-supplemented drinking water from the age of 3 weeks, followed by OVA sensitization and challenges as described. A,Ex vivo proliferation of SCFA-primed splenocytes in response to OVA restimulation. B,Ex vivo Treg cell differentiation of SCFA-primed splenocytes after OVA restimulation. C, Differentiation of CD4+ T cells to Treg cells after SCFA treatment in vitro. A and B, Each symbol represents 1 independently treated mouse. P values were determined by using an unpaired t test or 1-way ANOVA. ∗∗P < .01; ∗∗∗P < .001. Ctrl, Control.
Fig 5 SCFAs enhanced Treg cell differentiaion. Female BALB/c mice were given SCFA-supplemented drinking water from the age of 3 weeks, followed by OVA sensitization and challenges as described. A,Ex vivo proliferation of SCFA-primed splenocytes in response to OVA restimulation. B,Ex vivo Treg cell differentiation of SCFA-primed splenocytes after OVA restimulation. C, Differentiation of CD4+ T cells to Treg cells after SCFA treatment in vitro. A and B, Each symbol represents 1 independently treated mouse. P values were determined by using an unpaired t test or 1-way ANOVA. ∗∗P < .01; ∗∗∗P < .001. Ctrl, Control.CC BY-NC-ND · PubMed Central
Fig 6 MDSCs and Treg cells mediated the immunosuppressive effects of SCFAs. PMN-MDSCs and Mo-MDSCs from the lungs of the asthmatic mice were subjected to fluorescence-activated cell sorting by the expresson of CD11b, Ly6G, and Ly6C after aerosl OVA challenge. A, Microphotographs showed the morphology of Liu-stained PMN-MDSCs and Mo-MDSCs. Scale bar = 10 μm. B, Gene expressions of the FACS-sorted lung Mo-MDSCs and PMN-MDSCs. C, Suppression of OVA323-339-elicited CD4+ T-cell proliferation by MDSC subpopulations. Alternatively, to investigate induction of Treg cells by MDSCs, BM PMN-MDSCs and Mo-MDSCs were FACS–sorted and cocultured with CD4+ T cells or spleen cells. D, Differentiation of Treg cells from purified CD4+ T cells and splenocytes after MDSC coculture under nonspecific T-cell activation and antigen-specific (OVA) stimulation, respectively E, Cell contact–dependent induction of Treg cells by MDSCs was examined in a transwell coculture. F, Surface TGF-β expression by PMN-MDSCs after a 3-day coculture with CD4+ T cells and splenocytes was examined by flow cytometry. G, Induction of Treg cells by PMN-MDSCs in the presence of an TGF-β–blocking antibody (10 μg/mL). H, Chemokine expression by lung epithelial cells and in the BLAF after SCFA treatment. The data shown represent 1 of 3 independent experiments, each performed in triplicate. P values were determined by using an unpaired t test or 1-way ANOVA. ∗∗P < .01; ∗∗∗P < .001.
Fig 6 MDSCs and Treg cells mediated the immunosuppressive effects of SCFAs. PMN-MDSCs and Mo-MDSCs from the lungs of the asthmatic mice were subjected to fluorescence-activated cell sorting by the expresson of CD11b, Ly6G, and Ly6C after aerosl OVA challenge. A, Microphotographs showed the morphology of Liu-stained PMN-MDSCs and Mo-MDSCs. Scale bar = 10 μm. B, Gene expressions of the FACS-sorted lung Mo-MDSCs and PMN-MDSCs. C, Suppression of OVA323-339-elicited CD4+ T-cell proliferation by MDSC subpopulations. Alternatively, to investigate induction of Treg cells by MDSCs, BM PMN-MDSCs and Mo-MDSCs were FACS–sorted and cocultured with CD4+ T cells or spleen cells. D, Differentiation of Treg cells from purified CD4+ T cells and splenocytes after MDSC coculture under nonspecific T-cell activation and antigen-specific (OVA) stimulation, respectively E, Cell contact–dependent induction of Treg cells by MDSCs was examined in a transwell coculture. F, Surface TGF-β expression by PMN-MDSCs after a 3-day coculture with CD4+ T cells and splenocytes was examined by flow cytometry. G, Induction of Treg cells by PMN-MDSCs in the presence of an TGF-β–blocking antibody (10 μg/mL). H, Chemokine expression by lung epithelial cells and in the BLAF after SCFA treatment. The data shown represent 1 of 3 independent experiments, each performed in triplicate. P values were determined by using an unpaired t test or 1-way ANOVA. ∗∗P < .01; ∗∗∗P < .001.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Huang, M.-T., Chiu, C.-J., Tsai, C.-Y., Lee, Y.-R., Liu, W.-L., Chuang, H.-L., & Huang, M.-T.
Venue
Journal of Allergy and Clinical Immunology: Global
Publisher
Elsevier BV
Published
2023-11
Volume
2
Issue
4
Pages
100163
ISSN
2772-8293
DOI
10.1016/j.jacig.2023.100163
PMC
PMC10509984
Cited by
45
References
3
Language
en
Licence
Funders
  • National Science and Technology Council
  • Ministry of Science and Technology, Taiwan (108-2314-B-002-149, 109-2314-B-002-136, MOST 106-2314-B-002-190)
  • National Taiwan University Hospital (106-S3546, NTUH 105-04)

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