Fms-Like Tyrosine Kinase 3-Independent Dendritic Cells Are Major Mediators of Th2 Immune Responses in Allergen-Induced Asthmatic Mice

Abstract

Dendritic cells (DCs) are the main mediators of Th2 immune responses in allergic asthma, and Fms-like tyrosine kinase 3 ligand (Flt3L) is an important growth factor for the development and homeostasis of DCs. This study identified the DC populations that primarily cause the initiation and development of allergic lung inflammation using Fms-like tyrosine kinase 3 (Flt3) knockout (KO) mice with allergen-induced allergic asthma. We observed type 2 allergic lung inflammation with goblet cell hyperplasia in Flt3 KO mice, despite a significant reduction in total DCs, particularly CD103+ DCs, which was barely detected. In addition, bone marrow-derived dendritic cells (BMDCs) from Flt3 KO mice directed Th2 immune responses in vitro, and the adoptive transfer of these BMDCs exacerbated allergic asthma with more marked Th2 responses than that of BMDCs from wild-type (WT) mice. Furthermore, we found that Flt3L regulated the in vitro expression of OX40 ligand (OX40L) in DCs, which is correlated with DC phenotype in in vivo models. In conclusion, we revealed that Flt3-independent CD11b+ DCs direct Th2 responses with the elevated OX40L and are the primary cause of allergic asthma. Our findings suggest that Flt3 is required to control type 2 allergic inflammation.

Understanding the Mouse Model of Respiratory Allergic Diseases

“…에서 진행하면 폐로 항원이 쉽게 흡인되어 천식을 유도할 수 있다. 24,33) 비강 내 투여는 일반적으로 항원을 여러 차례 반복 해서 투여해야 염증반응이 충분히 유도되는 특성이 있어서, 천식 모델을 제작하기 위해서는 마취하에 기관지 내로 직접 항원을 투여하는 방법을 쓰기도 한다. 21,36) 이상의 방법은 마 취를 해야 할 뿐 아니라 마우스에게 침습적인 편이기에, 가습 기 챔버에 마우스를 위치시키고 항원을 분무시켜서 에어로졸 형태로 흡입하게 하여 투여하는 방법도 널리 사용된다.…”

“…• Not physiologic route of human sensitization Intranasal 15,28,29,32,33) • Many instillations required…”

OX40L–OX40 Signaling in Atopic Dermatitis

“…In a murine asthma model using repeated ovalbumin administration, OX40 deficiency resulted in a significant reduction of airway hyperreactivity and Th2 responses such as IL-4 and IgE production [26]. Fms-like tyrosine kinase 3 is a cardinal molecule for generating functional dendritic cells [27]. Respiratory syncytial virus infection also induces Th2-prone respiratory inflammation [28].…”