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Airway Epithelial Cell Activation and Remodeling

The airway epithelium plays a pathobiologic role in orchestrating inflammation and undergoes extensive remodeling in airway disease. Our lab is interested in understanding the functional implications of such remodeling and have approached this using airway epithelial cell cultures, single cell RNA-Seq from the human sino-nasal mucosa, and murine models of type 2 lung inflammation elicited by common aeroallergens. Through these studies we have found a profound plasticity in airway epithelial cells, with gene expression and differentiation finely reflecting their surrounding inflammatory milieu. Remarkably, once aberrant epithelial cell functions are established, they persist in part due to epigenetically altered epithelial progenitors [1]. Additionally, we have identified a novel feature of airway remodeling, the expansion of brush cells. This unique chemosensory epithelial cell population can activate subepithelial sensory nerves. We find that expansion of this population augments the proinflammatory capacity of the epithelium and is regulated by the receptor for leukotriene LTE4 CysLT3R [2]. Our ongoing interest is to understand the pathways driving airway epithelial cell development and function in health and disease.

  1. Ordovas-Montanes J, Dwyer DF, Nyquist SK, Buchheit KM, Vukovic M, Deb C, Wadsworth MH 2nd, Hughes TK, Kazer SW, Yoshimoto E, Cahill KN, Bhattacharyya N, Katz HR, Berger B, Laidlaw TM, Boyce JA, Barrett NA*, Shalek AK*. *These authors jointly supervised this work. Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature. 2018 Aug;560(7720):649-54.
  2. Bankova LG, Dwyer DF, Yoshimoto E, Ualiyeva S, McGinty JW, Raff H, von Moltke J, Kanaoka Y, Frank Austen K, Barrett NA. The cysteinyl leukotriene 3 receptor regulates expansion of IL-25-producing airway brush cells leading to type 2 inflammation. Sci Immunol. 2018 Oct 5;3(28).

Innate Immune Sensing in the Respiratory Tract

The laboratory has a long-standing interest in defining the immune pathways activated by common environmental insults such as dust mite and mold aeroallergens. Through fractionation of crude allergen extracts, signaling inhibition, and molecular approaches, we have defined key signaling pathways through which tissue-resident innate immune cells sense the external environment to pattern adaptive immunity. This includes a conserved role for the enzyme leukotriene C4 synthase (LTC4S) which is activated in dendritic cells [2] and mast cells [1], among other cell types, and generates pro-inflammatory lipid mediators, cysteinyl leukotrienes (cysLTs).  We have discovered that cysLT generation can be elicited by allergen-associated glycan recognition by the C-type lectin receptor, Dectin-2 [2, 3], and that this recognition plays a key role in both priming for Th2/Th17 immunity [4] and regulating effector phase inflammatory responses [5]. Our ongoing work includes defining additional innate immune pathways in the response to aeroallergens.

  1. Bankova, L.G., Lai, J., Yoshimoto, E., Boyce, J.A., Austen, K.F., Kanaoka, Y., and Barrett, N.A. Leukotriene E4 elicits respiratory epithelial cell mucin release through the G-protein-coupled receptor, GPR99. Proc Natl Acad Sci U S A. 2016 May 31;113(22):6242-7.
  2. Barrett NA, Maekawa A, Rahman OM, Austen KF, Kanaoka Y. Dectin-2 recognition
    of house dust mite triggers cysteinyl leukotriene generation by dendritic cells.
    J Immunol. 2009 Jan 15;182(2):1119-28.
  3. Barrett NA, Rahman OM, Fernandez JM, Parsons MW, Xing W, Austen KF, Kanaoka Y. Dectin-2 mediates Th2 immunity through the generation of cysteinyl leukotrienes. J Exp Med. 2011 Mar 14;208(3):593-604.
  4. Lee, MJ, Yoshimoto E, Saijo S, Iwakura Y, Lin X, Katz HR, Kanaoka Y, Barrett NA.  Phosphoinositide 3-Kinase δ Regulates Dectin-2 Signaling and the Generation of Th2 and Th17 Immunity. J Immunol. 2016 Jul 1;197(1):278-87.
  5. Parsons MW, Li L, Wallace AM, Lee MJ, Katz HR, Fernandez JM, Saijo S, Iwakura Y, Austen KF, Kanaoka Y, Barrett NA. Dectin-2 regulates the effector phase of house dust mite-elicited pulmonary inflammation independently from its role in sensitization. J Immunol. 2014 Feb 15;192(4):1361-71.

IgE-Independent Mast Cell Function

Mast cells are unique tissue-resident immunocytes that generate a wide repertoire of active mediators including cysLTs, amines, proteases, and cytokines.  The immune functions of these ancient cells, that preceded adaptive immunity, are poorly understood and the pathways for their tissue expansion and activation in disease remain unclear. We have used transcriptional methods including microarray  [1], RNA-seq, and single cell RNA-seq [4] and mouse models of allergic disease [2, 3] to understand their contribution to tissue homeostasis, host defense, and inflammation. Current work includes defining pathways that elicit their activation and maintenance in a variety of human diseases.

  1. Dwyer DF, Barrett NA*, Austen KF*. Expression profiling of constitutive mast cells reveals a unique identity within the immune system. *These authors jointly supervised this work. Nat Immunol. 2016 Jul;17(7):878-87.
  2. Bankova, L.G., Lai, J., Yoshimoto, E., Boyce, J.A., Austen, K.F., Kanaoka, Y., and Barrett, N.A. (2016). Leukotriene E4 elicits respiratory epithelial cell mucin release through the G-protein-coupled receptor, GPR99. Proc Natl Acad Sci U S A. 2016 May 31;113(22):6242-7.
  3. Liu T, Barrett NA, Kanaoka Y, Yoshimoto E, Laidlaw TM, Garofalo D, Feng C, Boyce JA. Type 2 cysteinyl leukotriene receptors drive aspirin sensitivity and eosinophilic immunopathology. J Immunol. 2018 Feb 1; 200(3):915-27.
  4. Ordovas-Montanes J, Dwyer DF, Nyquist SK, Buchheit KM, Vukovic M, Deb C, Wadsworth MH 2nd, Hughes TK, Kazer SW, Yoshimoto E, Cahill KN, Bhattacharyya N, Katz HR, Berger B, Laidlaw TM, Boyce JA, Barrett NA*, Shalek AK*. *These authors jointly supervised this work. Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature. 2018 Aug;560(7720):649-54.
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