STAT6 Regulates the Development of Eosinophilic versus Neutrophilic Asthma in Response to Alternaria alternata.
Human asthma is a heterogeneous disease characterized by the expression of both Th2 and Th17 cytokines. In vitro and in vivo studies have shown a reciprocal regulation between Th2 and Th17 pathways, suggesting a potential induction of neutrophil-promoting Th17 inflammation in the absence of a Th2 response. Alternaria alternata is a clinically relevant allergen that is associated with severe and fatal asthma exacerbations. Exposure to A. alternata is characterized by a predominant Th2 response, but can also induce the production of factors associated with Th17 responses (e.g., CXCL8) from epithelial cells. Using a mouse model, we found that wild-type mice develop an eosinophilic Th2 airway disease in response to A. alternata exposure, whereas IL-4-, IL-13-, and STAT6-deficient mice exhibit a primarily neutrophilic response. Neutrophilic asthma in STAT6-/-mice was accompanied by elevated lung levels of TNF-α, CXCL1, CXCL2, and CXCL5, and was steroid resistant. Neutralization of Th17 signaling only partially reduced neutrophil numbers and total airway inflammation. Airway neutrophilia developed in RAG-deficient and CD4-depleted BALB/c mice, suggesting that the suppression of neutrophil responses is dependent on Th2 cytokine production by T cells and that airway neutrophilia is primarily an innate response to allergen. These results highlight the importance of combination therapies for treatment of asthma and establish a role for factors other than IL-17 as targets for neutrophilic asthma.
Department of Immunology, University of Washington, Seattle, WA 98101.|Immunology Program, Benaroya Research Institute, Seattle, WA 98101; and.
Andrea C
AC
Valladao
Department of Comparative Medicine, University of Washington, Seattle, WA 98101.
Charles W
0000-0002-1037-3244
CW
Frevert
Immunology Program, Benaroya Research Institute, Seattle, WA 98101; and.
Lisa K
0000-0002-3890-9290
LK
Koch
Department of Immunology, University of Washington, Seattle, WA 98101.|Immunology Program, Benaroya Research Institute, Seattle, WA 98101; and.
Daniel J
DJ
Campbell
Department of Immunology, University of Washington, Seattle, WA 98101; sziegler@benaroyaresearch.org.|Immunology Program, Benaroya Research Institute, Seattle, WA 98101; and.
Steven F
SF
Ziegler
D000485:Allergens / Q000276:immunology; D000528:Alternaria / Q000276:immunology*; D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology; D001249:Asthma / Q000276:immunology*; D002457:Cell Extracts / Q000276:immunology; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology*; D005260:Female; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018183:Transplantation Chimera
D000485:Allergens; D000946:Antigens, Fungal; D002457:Cell Extracts; D018793:Interleukin-13; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4