The allergic asthma phenotype is affected by CD4+ T helper cell-produced cytokines, with severe clinical asthma and mouse models of severe disease associated with IL-17 production, neutrophilia, and glucocorticoid resistance. We demonstrate that Serum Amyloid A (SAA), an endogenous mediator produced by the airway epithelium, induces innate immune cytokine production, neutrophilia, and polarizes Th17 responses to innocuous inhaled antigens. We have reported that SAA stimulates the extracellular Toll-Like Receptor 2 (TLR2) and the intracellular NOD-like receptor, Nlrp3, which are required for the secretion of IL-1?, a Th17- polarizing cytokine. In addition, pharmacologic antagonism of the IL-1 receptor prevents IL-17 production in vitro and IL-1 receptor-deficient (IL-1R?-/-) mice do not undergo Th17 polarization in response to SAA3-inducing exposures that promote allergic sensitization to ovalbumin or to combined administration of SAA and ovalbumin. Finally, SAA exacerbates allergen-induced airway hyper-responsiveness to methacholine and enhances airway neutrophilia in allergen sensitized and challenged mice. We hypothesize that pulmonary SAA (SAA3 in mice) is an epithelial-derived endogenous mediator of allergic asthma severity that functions to polarize IL-1-dependent Th17 responses that contribute to severe disease.
In Specific Aim 1 we will determine quantitative and qualitative patterns of Saa3 expression and SAA3 production during the development of allergic asthma in mouse models of disease.
In Specific Aim 2 we will establish the effects of SAA on the antigen-specific CD4+ T cell adaptive immune response in vitro and in vivo using wildtype and inducible airway epithelial SAA3-secreting mice. We will determine whether SAA3 promotes Th17 polarization, whether the receptors TLR2, Nlrp3, IL-1R?, and FPR2 (Formyl Protein Receptor 2, which has been shown to induce leukocyte chemotaxis to SAA) are involved, whether the activity is directly upon T cells, and whether the effect of SAA3 is glucorticoid-sensitive.
In Specific Aim 3 we will establish in vivo the necessity (using Saa3 silencing, SAA3 neutralization, and SAA3 knockout mice) and sufficiency (using SAA instillation and inducible SAA3- producing transgenic mice) of SAA3 for augmentation of allergic asthma severity, addressing mechanisms implicated from the previous specific aims by which SAA3 worsens lung physiologic and structural allergic asthma phenotypes, including glucocorticoid responsiveness. Understanding the effect of endogenous mediators on Th17-inducing responses in allergic asthma will provide unprecedented insight into the varied nature of the asthma syndrome and may provide novel targets for the development of therapeutics.

Public Health Relevance

While the reasons why some patients have a severe form of allergic asthma remain unknown, the pathophysiologic phenotype is associated with a Th17-driven adaptive immune response and glucocorticoid unresponsiveness. Using several novel animal models, we will dissect cellular and molecular mechanisms through which a pulmonary epithelial-derived endogenous molecule, Serum Amyloid A3 (SAA3), affects these features of severe asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL107291-03
Application #
8616089
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2012-04-01
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
$343,125
Indirect Cost
$118,125
Name
University of Vermont & St Agric College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Ather, Jennifer L; Poynter, Matthew E (2018) Serum amyloid A3 is required for normal weight and immunometabolic function in mice. PLoS One 13:e0192352
Burgess, Edward J; Hoyt, Laura R; Randall, Matthew J et al. (2018) Bacterial Lipoproteins Constitute the TLR2-Stimulating Activity of Serum Amyloid A. J Immunol 201:2377-2384
Ather, Jennifer L; Dienz, Oliver; Boyson, Jonathan E et al. (2018) Serum Amyloid A3 is required for normal lung development and survival following influenza infection. Sci Rep 8:16571
Hoyt, Laura R; Randall, Matthew J; Ather, Jennifer L et al. (2017) Mitochondrial ROS induced by chronic ethanol exposure promote hyper-activation of the NLRP3 inflammasome. Redox Biol 12:883-896
Lundblad, Lennart K A; Gülec, Nazey; Poynter, Matthew E et al. (2017) The role of iNKT cells on the phenotypes of allergic airways in a mouse model. Pulm Pharmacol Ther 45:80-89
Dixon, Anne E; Poynter, Matthew E (2016) Mechanisms of Asthma in Obesity. Pleiotropic Aspects of Obesity Produce Distinct Asthma Phenotypes. Am J Respir Cell Mol Biol 54:601-8
Poynter, Matthew E (2016) Do insights from mice imply that combined Th2 and Th17 therapies would benefit select severe asthma patients? Ann Transl Med 4:505
Poynter, Matthew E; Irvin, Charles G (2016) Interleukin-6 as a biomarker for asthma: hype or is there something else? Eur Respir J 48:979-981
Ubags, Niki D J; Burg, Elianne; Antkowiak, Maryellen et al. (2016) A Comparative Study of Lung Host Defense in Murine Obesity Models. Insights into Neutrophil Function. Am J Respir Cell Mol Biol 55:188-200
Dalsgaard, Thomas; Sonkusare, Swapnil K; Teuscher, Cory et al. (2016) Pharmacological inhibitors of TRPV4 channels reduce cytokine production, restore endothelial function and increase survival in septic mice. Sci Rep 6:33841

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