Systemic FasL neutralization increases eosinophilic inflammation in a mouse model of asthma

S. K. Sharma, F. A. Almeida, S. Kierstein, L. Hortobagyi, T. Lin, A. Larkin, J. Peterson, H. Yagita, J. G. Zangrilli, Angela Franciska Haczku

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background: Eosinophils and lymphocytes are pathogenically important in allergic inflammation and sensitive to Fas-mediated apoptosis. Fas ligand (FasL) activity therefore should play a role in regulating the allergic immune response. We aimed to characterize the role of FasL expression in airway eosinophilia in Aspergillus fumigatus (Af)-induced sensitization and to determine whether FasL neutralization alters the inflammatory response. Methods: Sensitized Balb/c mice were killed before (day 0) and 1, 7 and 10 days after a single intranasal challenge with Af. Animals received either neutralizing antibody to FasL (clone MFL4) or irrelevant hamster IgG via intraperitoneal injection on days -1 and 5. FasL expression, BAL and tissue inflammatory cell and cytokine profile, and apoptosis were assessed. Results: Postchallenge FasL gene expression in BAL cells and TUNEL positivity in the airways coincided with the height of inflammatory cell influx on day 1, while soluble FasL protein was released on day 7, preceding resolution of the inflammatory changes. Although eosinophil numbers showed a negative correlation with soluble FasL levels in the airways, MBP + eosinophils remained TUNEL negative in the submucosal tissue, throughout the 10-day period after Af challenge. Systemic FasL neutralization significantly enhanced BAL and tissue eosinophil counts. This effect was associated with increased activation of T cells and release of IL-5, IL-9, and GM-CSF in the BAL fluid of mice, indicating an involvement of pro-eosinophilic survival pathways. Conclusions: FasL activity may play an active role in resolving eosinophilic inflammation through regulating T cells and pro-eosinophilic cytokine release during the allergic airway response.

Original languageEnglish (US)
Pages (from-to)328-335
Number of pages8
JournalAllergy: European Journal of Allergy and Clinical Immunology
Volume67
Issue number3
DOIs
StatePublished - Mar 2012
Externally publishedYes

Fingerprint

Fas Ligand Protein
Asthma
Inflammation
Dimercaprol
Eosinophils
Aspergillus fumigatus
In Situ Nick-End Labeling
Interleukin-9
Apoptosis
Cytokines
T-Lymphocytes
Interleukin-5
Eosinophilia
Granulocyte-Macrophage Colony-Stimulating Factor
Neutralizing Antibodies
Intraperitoneal Injections
Cricetinae
Clone Cells
Immunoglobulin G
Lymphocytes

Keywords

  • allergen challenge
  • animal models
  • asthma
  • eosinophil
  • Fas ligand

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Systemic FasL neutralization increases eosinophilic inflammation in a mouse model of asthma. / Sharma, S. K.; Almeida, F. A.; Kierstein, S.; Hortobagyi, L.; Lin, T.; Larkin, A.; Peterson, J.; Yagita, H.; Zangrilli, J. G.; Haczku, Angela Franciska.

In: Allergy: European Journal of Allergy and Clinical Immunology, Vol. 67, No. 3, 03.2012, p. 328-335.

Research output: Contribution to journalArticle

Sharma, SK, Almeida, FA, Kierstein, S, Hortobagyi, L, Lin, T, Larkin, A, Peterson, J, Yagita, H, Zangrilli, JG & Haczku, AF 2012, 'Systemic FasL neutralization increases eosinophilic inflammation in a mouse model of asthma', Allergy: European Journal of Allergy and Clinical Immunology, vol. 67, no. 3, pp. 328-335. https://doi.org/10.1111/j.1398-9995.2011.02763.x
Sharma, S. K. ; Almeida, F. A. ; Kierstein, S. ; Hortobagyi, L. ; Lin, T. ; Larkin, A. ; Peterson, J. ; Yagita, H. ; Zangrilli, J. G. ; Haczku, Angela Franciska. / Systemic FasL neutralization increases eosinophilic inflammation in a mouse model of asthma. In: Allergy: European Journal of Allergy and Clinical Immunology. 2012 ; Vol. 67, No. 3. pp. 328-335.
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abstract = "Background: Eosinophils and lymphocytes are pathogenically important in allergic inflammation and sensitive to Fas-mediated apoptosis. Fas ligand (FasL) activity therefore should play a role in regulating the allergic immune response. We aimed to characterize the role of FasL expression in airway eosinophilia in Aspergillus fumigatus (Af)-induced sensitization and to determine whether FasL neutralization alters the inflammatory response. Methods: Sensitized Balb/c mice were killed before (day 0) and 1, 7 and 10 days after a single intranasal challenge with Af. Animals received either neutralizing antibody to FasL (clone MFL4) or irrelevant hamster IgG via intraperitoneal injection on days -1 and 5. FasL expression, BAL and tissue inflammatory cell and cytokine profile, and apoptosis were assessed. Results: Postchallenge FasL gene expression in BAL cells and TUNEL positivity in the airways coincided with the height of inflammatory cell influx on day 1, while soluble FasL protein was released on day 7, preceding resolution of the inflammatory changes. Although eosinophil numbers showed a negative correlation with soluble FasL levels in the airways, MBP + eosinophils remained TUNEL negative in the submucosal tissue, throughout the 10-day period after Af challenge. Systemic FasL neutralization significantly enhanced BAL and tissue eosinophil counts. This effect was associated with increased activation of T cells and release of IL-5, IL-9, and GM-CSF in the BAL fluid of mice, indicating an involvement of pro-eosinophilic survival pathways. Conclusions: FasL activity may play an active role in resolving eosinophilic inflammation through regulating T cells and pro-eosinophilic cytokine release during the allergic airway response.",
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T1 - Systemic FasL neutralization increases eosinophilic inflammation in a mouse model of asthma

AU - Sharma, S. K.

AU - Almeida, F. A.

AU - Kierstein, S.

AU - Hortobagyi, L.

AU - Lin, T.

AU - Larkin, A.

AU - Peterson, J.

AU - Yagita, H.

AU - Zangrilli, J. G.

AU - Haczku, Angela Franciska

PY - 2012/3

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N2 - Background: Eosinophils and lymphocytes are pathogenically important in allergic inflammation and sensitive to Fas-mediated apoptosis. Fas ligand (FasL) activity therefore should play a role in regulating the allergic immune response. We aimed to characterize the role of FasL expression in airway eosinophilia in Aspergillus fumigatus (Af)-induced sensitization and to determine whether FasL neutralization alters the inflammatory response. Methods: Sensitized Balb/c mice were killed before (day 0) and 1, 7 and 10 days after a single intranasal challenge with Af. Animals received either neutralizing antibody to FasL (clone MFL4) or irrelevant hamster IgG via intraperitoneal injection on days -1 and 5. FasL expression, BAL and tissue inflammatory cell and cytokine profile, and apoptosis were assessed. Results: Postchallenge FasL gene expression in BAL cells and TUNEL positivity in the airways coincided with the height of inflammatory cell influx on day 1, while soluble FasL protein was released on day 7, preceding resolution of the inflammatory changes. Although eosinophil numbers showed a negative correlation with soluble FasL levels in the airways, MBP + eosinophils remained TUNEL negative in the submucosal tissue, throughout the 10-day period after Af challenge. Systemic FasL neutralization significantly enhanced BAL and tissue eosinophil counts. This effect was associated with increased activation of T cells and release of IL-5, IL-9, and GM-CSF in the BAL fluid of mice, indicating an involvement of pro-eosinophilic survival pathways. Conclusions: FasL activity may play an active role in resolving eosinophilic inflammation through regulating T cells and pro-eosinophilic cytokine release during the allergic airway response.

AB - Background: Eosinophils and lymphocytes are pathogenically important in allergic inflammation and sensitive to Fas-mediated apoptosis. Fas ligand (FasL) activity therefore should play a role in regulating the allergic immune response. We aimed to characterize the role of FasL expression in airway eosinophilia in Aspergillus fumigatus (Af)-induced sensitization and to determine whether FasL neutralization alters the inflammatory response. Methods: Sensitized Balb/c mice were killed before (day 0) and 1, 7 and 10 days after a single intranasal challenge with Af. Animals received either neutralizing antibody to FasL (clone MFL4) or irrelevant hamster IgG via intraperitoneal injection on days -1 and 5. FasL expression, BAL and tissue inflammatory cell and cytokine profile, and apoptosis were assessed. Results: Postchallenge FasL gene expression in BAL cells and TUNEL positivity in the airways coincided with the height of inflammatory cell influx on day 1, while soluble FasL protein was released on day 7, preceding resolution of the inflammatory changes. Although eosinophil numbers showed a negative correlation with soluble FasL levels in the airways, MBP + eosinophils remained TUNEL negative in the submucosal tissue, throughout the 10-day period after Af challenge. Systemic FasL neutralization significantly enhanced BAL and tissue eosinophil counts. This effect was associated with increased activation of T cells and release of IL-5, IL-9, and GM-CSF in the BAL fluid of mice, indicating an involvement of pro-eosinophilic survival pathways. Conclusions: FasL activity may play an active role in resolving eosinophilic inflammation through regulating T cells and pro-eosinophilic cytokine release during the allergic airway response.

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KW - asthma

KW - eosinophil

KW - Fas ligand

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