Balancing immune responses in lung pathology
For a long time, asthma was largely considered a single, T-helper 2 (Th2) driven inflammatory disease, with eosinophils being the characteristic effector cell population. However, it is now clear there is a heterogeneity of asthma phenotypes with a complex array of T cell responses, innate and adaptive responses as well as a variety of effector cells all contributing to pathology.
In severe asthmatics inflammation is generally defined by neutrophilic or mixed neutrophil/eosinophil airway infiltrates, along with increased IL-17 and airway remodelling. Severe asthma with neutrophil predominance or mixed phenotype has proved challenging to treat, with the patients often becoming unresponsive/resistant to steroid treatments. Unlike eosinophilia and adaptive Th2 responses, the contribution of neutrophils, innate immune responses and IL-17 to chronic allergic airway inflammation and remodelling is poorly understood.
Expression of chitinase-like protein Ym1 (red), in alveolar macrophages and epithelial cells during N.brasiliensis infection driven type 2 inflammation in the lung. Staining also shows co-expression of Th2 regulated cytokine RELMa (green) and DNA staining (blue).
We have recently shown that the chitinase-like protein (CLP) family can drive alveolar neutrophil recruitment through increased IL-1/IL-18 expression and expansion of an innate population of IL-17-producing gamma delta T cells. Considering CLP expression is strongly associated with Th2 pathology and type 2 inflammatory diseases are not normally characterized by neutrophilia, this was a rather surprising finding and provides a potential link between type 2 responses in allergic inflammation and enhanced neutrophilia.
It is unlikely that simply increased IL-17 and neutrophil numbers in the lungs alone explain the degree of pathology in severe asthma. Rather, mounting evidence would suggest that IL-17 and/or neutrophils might exacerbate type 2 pathology. Indeed, further to effects on neutrophilia, CLPs also alter the production of type 2 cytokines during lung inflammation. As a consequence of increased pro-fibrotic IL-13 levels and also through direct, as yet undefined actions, CLPs will promote repair/remodelling of lung tissue, a dominant trait of severe asthma. Therefore, we believe CLPs are key regulators of both innate and adaptive immune responses, pushing the boundaries of asthma pathology.
Using a range of technologies including bio-imaging, multi-parameter flow cytometry, molecular techniques, in vivo and in vitro models, we aim to investigate the key initiating immune mechanisms that influence the development of allergic airway inflammation and ask questions about the relationship between IL-17/neutrophils and Th2 pathology. We will also investigate whether CLPs may be the missing link that tips the balance of type 2 airway inflammation towards a more severe phenotype with neutrophil dominance and chronic remodelling of the airways.
Schematic diagram of some of the proposed functions of chitinase-like proteins and the contribution of different immune responses during allergic airway inflammation and remodelling.
Knipper JA, Willenborg S, Brinckmann J, Bloch W, Maaß T, Wagener R, Krieg T, Sutherland TE, Munitz A, Rothenberg ME, Niehoff A, Richardson R, Hammerschmidt M, Allen JE, Eming SA. (2015) Interleukin-4 Receptor α Signaling in Myeloid Cells Controls Collagen Fibril Assembly in Skin Repair. Immunity. 43(4): 803-16.
Allen JE, Sutherland TE, Rückerl D. (2015) IL-17 and neutrophils: unexpected players in the type 2 immune response. Curr Opin Immunol. 34: 99-106. Review
Sutherland TE*, Logan N, Rückerl D, Humbles AA, Allan SM, Papayannopoulos V, Stockinger B, Maizels RM, Allen JE*. (2014) Chitinase-like proteins promote IL-17-mediated neutrophilia in a tradeoff between nematode killing and host damage. Nat Immunol. 15(12): 1116-25. *Joint corresponding author
Osborne LC, Monticelli LA, Nice TJ, Sutherland TE, Siracusa MC, Hepworth MR, Tomov VT, Kobuley D, Tran SV, Bittinger K, Bailey AG, Laughlin AL, Boucher JL, Wherry EJ, Bushman FD, Allen JE, Virgin HW, Artis D. (2014) Coinfection. Virus-helminth coinfection reveals a microbiota-independent mechanism of immunomodulation. Science. 345(6196): 578-82.
Allen JE, Sutherland TE. (2014) Host protective roles of type 2 immunity: parasite killing and tissue repair, flip sides of the same coin. Semin Immunol. 26(4): 329-40. Review.
McSorley HJ, O'Gorman MT, Blair N, Sutherland TE, Filbey KJ, Maizels RM. (2012) Suppression of type 2 immunity & allergic airway inflammation by secreted products of the helminth Heligmosomoides polygyrus. Eur J Immunol. 42(10): 2667-82.
Sutherland TE, Andersen OA, Betou M, Eggleston IM, Maizels RM, van Aalten D, Allen JE. (2011) Analyzing airway inflammation with chemical biology: dissection of acidic mammalian chitinase function with a selective drug-like inhibitor. Chem Biol. 18(5): 569-79.