Pathogenic changes in group 2 innate lymphoid cells (ILC2s) in a steroid-insensitive asthma model of mice.

Abstract

A certain population of asthma patients is resistant to steroid therapy, whereas the mechanisms remain unclear. One of characteristic features of steroid-resistant asthma patients is severe airway eosinophilia based on type-2 inflammation. Aims of this study were: 1) to develop a murine model of steroid-resistant asthma, 2) to elucidate that predominant cellular source of a type-2 cytokine, IL-5 was group 2 innate lymphoid cells (ILC2s), 3) to analyze pathogenic alteration of ILC2s in the severe asthma, and 4) to evaluate therapeutic potential of anti-IL-5 monoclonal antibody (mAb) on the steroid-resistant asthma. Ovalbumin (OVA)-sensitized BALB/c mice were intratracheally challenged with OVA at 5 or 500 μg/animal 4 times. Development of airway eosinophilia and remodeling in 5-μg OVA model were significantly suppressed by 1 mg/kg dexamethasone, whereas those in 500-μg OVA model were relatively insensitive to the dose of dexamethasone. ILC2s isolated from the lung of the steroid-insensitive model (500-μg OVA) produced significantly larger amounts of IL-5 in response to IL-33/TSLP than ILC2s from the steroid-sensitive model (5-μg OVA). Interestingly, TSLP receptor expression on ILC2s was up-regulated in the steroid-insensitive model. Treatment with anti-IL-5 mAb in combination with dexamethasone significantly suppressed the airway remodeling of the steroid-insensitive model. In conclusion, multiple intratracheal administration of a high dose of antigen induced steroid-insensitive asthma in sensitized mice. IL-5 was mainly produced from ILC2s, phenotype of which had been pathogenically altered probably through the up-regulation of TSLP receptors. IL-5 blockage could be a useful therapeutic strategy for steroid-resistant asthma.

• Authors: Masaya Matsuda, Yoshiyuki Tanaka, Hayato Shimora, Naoki Takemoto, Miku Nomura, Ryogo Terakawa, Kennosuke Hashimoto, Harumi Sakae, Akira Kanda, Hiroshi Iwai, Kazuyuki Kitatani, Takeshi Nabe
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 916 Pg. 174732 (Feb 05 2022) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 34971621 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Cytokines
• Steroids
• Ovalbumin

Topics

• Animals
• Asthma
• Cytokines (metabolism)
• Disease Models, Animal
• Immunity, Innate
• Lung (metabolism)
• Lymphocytes
• Mice
• Mice, Inbred BALB C
• Ovalbumin
• Steroids (therapeutic use)