Different endotypes of asthma were described in human. Atopic asthma is a T-helper 2 (Th2)-mediated disease consisting mainly of an eosinophilic inflammation in the airways. Other endotypes show neutrophilic inflammation of the airways that is probably based on a Th17 response. There are several mouse models described in the literature to study the Th2 polarized eosinophilic disease, however, only a few models are available which characterize the neutrophilic endotype. The aim of this study was to compare both endotypes in relation to the severity of the allergen-induced inflammation. Groups of either Balb/c or DO11.10 mice were sensitized with ovalbumin (OVA) adsorbed to aluminum hydroxide. Mice were subsequently challenged with OVA for different periods of time. They were evaluated for airway hyperreactivity (AHR), cytokine production, airway inflammation, and remodeling of the airways. As expected, Balb/c mice developed a Th2 response with AHR, eosinophilic airway inflammation, and allergen-specific IgE and IgG1. By contrast DO11.10 mice showed a mixed Th1/Th17 response with strong neutrophilic airway inflammation, IgG2a, but only limited induction of AHR. While Balb/c mice showed remodeling of the airways with subepithelial fibrosis and goblet cell metaplasia, airway remodeling in DO11.10 mice was marginal. Both airway inflammation and remodeling resolved after prolonged periods of challenge in both models. In conclusion, strong allergen-induced airway remodeling in mice seems to be triggered by the specific conditions arising from infiltration with eosinophilic granulocytes in the lung. A Th1/Th17 response leading to neutrophilic inflammation does not seem to be sufficient to induce pronounced airway remodeling.

1.
Hough KP, Curtiss ML, Blain TJ, Liu RM, Trevor J, Deshane JS, et al. Airway remodeling in asthma.
Front Med
. 2020;7:191.
2.
Agache I, Akdis C, Jutel M, Virchow JC. Untangling asthma phenotypes and endotypes.
Allergy
. 2012;67(7):835–46.
3.
Pillai RR, Divekar R, Brasier A, Bhavnani S, Calhoun WJ. Strategies for molecular classification of asthma using bipartite network analysis of cytokine expression.
Curr Allergy Asthma Rep
. 2012;12(5):388–95.
4.
Al-Alawi M, Hassan T, Chotirmall SH. Transforming growth factor β and severe asthma: a perfect storm.
Respiratory Med
. 2014;108(10):1409–23.
5.
Tsai HC, Velichko S, Hung LY, Wu R. IL-17A and Th17 cells in lung inflammation: an update on the role of Th17 cell differentiation and IL-17R signaling in host defense against infection.
Clin Dev Immunol
. 2013;2013:267971–12.
6.
Martin RA, Hodgkins SR, Dixon AE, Poynter ME. Aligning mouse models of asthma to human endotypes of disease.
Respirology
. 2014;19(6):823–33.
7.
Zosky GR, Sly PD. Animal models of asthma.
Clin Exp Allergy
. 2007;37(7):973–88.
8.
Peters M, Köhler-Bachmann S, Lenz-Habijan T, Bufe A. Influence of an allergen-specific Th17 response on remodeling of the airways.
Am J Respir Cell Mol Biol
. 2016;54(3):350–8.
9.
Lemaire MM, Dumoutier L, Warnier G, Uyttenhove C, van Snick J, de Heusch M, et al. Dual TCR expression biases lung inflammation in DO11.10 transgenic mice and promotes neutrophilia via microbiota-induced Th17 differentiation.
J Immunol
. 2011;187(7):3530–7.
10.
Saparov A, Kraus LA, Cong Y, Marwill J, Xu XY, Elson CO, et al. Memory/effector T cells in TCR transgenic mice develop via recognition of enteric antigens by a second, endogenous TCR.
Int Immunol
. 1999;11(8):1253–64.
11.
Pelletier M, Maggi L, Micheletti A, Lazzeri E, Tamassia N, Costantini C, et al. Evidence for a cross-talk between human neutrophils and Th17 cells.
Blood
. 2010;115(2):335–43.
12.
Knott PG, Gater PR, Bertrand CP. Airway inflammation driven by antigen-specific resident lung CD4(+) T cells in alphabeta-T cell receptor transgenic mice.
Am J Respir Crit Care Med
. 2000;161(4):1340–8.
13.
Kuruvilla ME, Lee FE, Lee GB. Understanding asthma phenotypes, endotypes, and mechanisms of disease.
Clin Rev Allergy Immunol
. 2019;56(2):219–33.
14.
Mitsdoerffer M, Lee Y, Jäger A, Kim HJ, Korn T, Kolls JK, et al. Proinflammatory T helper type 17 cells are effective B-cell helpers.
Proc Natl Acad Sci U S A
. 2010;107(32):14292–7.
15.
Gagliani N, Vesely MCA, Iseppon A, Brockmann L, Xu H, Palm NW, et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation.
Nature
. 2015;523(7559):221–5.
16.
Vignola AM, Riccobono L, Mirabella A, Profita M, Chanez P, Bellia V, et al. Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis.
Am J Respir Crit Care Med
. 1998;158(6):1945–50.
17.
Royce SG, Cheng V, Samuel CS, Tang ML. The regulation of fibrosis in airway remodeling in asthma.
Mol Cell Endocrinol
. 2012;351(2):167–75.
18.
Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.
Nat Immunol
. 2005;6(11):1133–41.
19.
Doherty T, Broide D. Cytokines and growth factors in airway remodeling in asthma.
Curr Opin Immunol
. 2007;19(6):676–80.
20.
Danahay H, Pessotti AD, Coote J, Montgomery BE, Xia D, Wilson A, et al. Notch2 is required for inflammatory cytokine-driven goblet cell metaplasia in the lung.
Cell Rep
. 2015;10(2):239–52.
21.
van Hove CL, Maes T, Joos GF, Tournoy KG. Prolonged inhaled allergen exposure can induce persistent tolerance.
Am J Respir Cell Mol Biol
. 2007;36(5):573–84.
22.
Murdoch JR, Lloyd CM. Resolution of allergic airway inflammation and airway hyperreactivity is mediated by IL-17-producing (gamma) (delta) T cells.
Am J Respir Crit Care Med
. 2010;182(4):464–76.
23.
Schnyder-Candrian S, Togbe D, Couillin I, Mercier I, Brombacher F, Quesniaux V, et al. Interleukin-17 is a negative regulator of established allergic asthma.
J Exp Med
. 2006;203(12):2715–25.
24.
Wilson RH, Whitehead GS, Nakano H, Free ME, Kolls JK, Cook DN. Allergic sensitization through the airway primes Th17-dependent neutrophilia and airway hyperresponsiveness.
Am J Respir Crit Care Med
. 2009;180(8):720–30.
25.
Wakashin H, Hirose K, Maezawa Y, Kagami S, Suto A, Watanabe N, et al. IL-23 and Th17 cells enhance Th2-cell-mediated eosinophilic airway inflammation in mice.
Am J Respir Crit Care Med
. 2008;178(10):1023–32.
26.
Neunkirchner A, Kratzer B, Köhler C, Smole U, Mager LF, Schmetterer KG, et al. Genetic restriction of antigen-presentation dictates allergic sensitization and disease in humanized mice.
EBioMedicine
. 2018;31:66–78.
27.
Denning TL, Norris BA, Medina-Contreras O, Manicassamy S, Geem D, Madan R, et al. Functional specializations of intestinal dendritic cell and macrophage subsets that control Th17 and regulatory T cell responses are dependent on the T cell/APC ratio, source of mouse strain, and regional localization.
J Immunol
. 2011;187(2):733–47.
28.
Schramm CM, Puddington L, Wu C, Guernsey L, Gharaee-Kermani M, Phan SH, et al. Chronic inhaled ovalbumin exposure induces antigen-dependent but not antigen-specific inhalational tolerance in a murine model of allergic airway disease.
Am J Pathol
. 2004;164(1):295–304.
29.
Kabbur PM, Carson WF, Guernsey L, Secor ER, Thrall RS, Schramm CM. Interleukin-10 does not mediate inhalational tolerance in a chronic model of ovalbumin-induced allergic airway disease.
Cell Immunol
. 2006;239(1):67–74.
30.
Moerch U, Haahr Hansen M, Vest Hansen NJ, Rasmussen LK, Oleksiewicz MB, Frandsen TP, et al. Allergen-specific polyclonal antibodies reduce allergic disease in a mouse model of allergic asthma.
Int Arch Allergy Immunol
. 2006;140(3):261–9.
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