Remote allergen exposure elicits eosinophil infiltration into allergen nonexposed mucosal organs and primes for allergic inflammation


The natural history of allergic diseases suggests bidirectional and progressive relationships between allergic disorders of the skin, lung, and gut indicative of mucosal organ crosstalk. However, impacts of local allergic inflammation on the cellular landscape of remote mucosal organs along the skin:lung:gut axis are not yet known. Eosinophils are tissue-dwelling innate immune leukocytes associated with allergic diseases. Emerging data suggest heterogeneous phenotypes of tissue-dwelling eosinophils contribute to multifaceted roles that favor homeostasis or disease. This study investigated the impact of acute local allergen exposure on the frequency and phenotype of tissue eosinophils within remote mucosal organs. Our findings demonstrate allergen challenge to skin, lung, or gut elicited not only local eosinophilic inflammation, but also increased the number and frequency of eosinophils within remote, allergen nonexposed lung, and intestine. Remote allergen-elicited lung eosinophils exhibited an inflammatory phenotype and their presence associated with enhanced susceptibility to airway inflammation induced upon subsequent inhalation of a different allergen. These data demonstrate, for the first time, a direct effect of acute allergic inflammation on the phenotype and frequency of tissue eosinophils within antigen nonexposed remote mucosal tissues associated with remote organ priming for allergic inflammation.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Mouse models of acute local and systemic eosinophilic infiltration.
Fig. 2: Epicutaneous or endotracheal allergen challenge elicits an increase in eosinophils within remote, allergen nonexposed intestine.
Fig. 3: Epicutaneous or intragastric allergen challenge elicits an increase in eosinophils within remote, allergen nonexposed lung.
Fig. 4: Numbers intestinal eosinophils, but not lung eosinophils, remain elevated up to 11 days following skin allergen challenge.
Fig. 5: Oral allergen-elicited lung eosinophils exhibit an inflammatory phenotype and their accumulation is accompanied by increased mucus production.
Fig. 6: Remote allergen challenge primes for respiratory allergic disease.


  1. 1.

    Bantz, S. K., Zhu, Z. & Zheng, T. The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. J. Clin. Cell Immunol. 5, 202 (2014).

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Guilbert, T. W. et al. Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthma. J. Allergy Clin. Immunol. 114, 1282–1287 (2004).

    Article  Google Scholar 

  3. 3.

    Gustafsson, D., Sjoberg, O. & Foucard, T. Development of allergies and asthma in infants and young children with atopic dermatitis–a prospective follow-up to 7 years of age. Allergy 55, 240–245 (2000).

    CAS  Article  Google Scholar 

  4. 4.

    Kapoor, R. et al. The prevalence of atopic triad in children with physician-confirmed atopic dermatitis. J. Am. Acad. Dermatol. 58, 68–73 (2008).

    Article  Google Scholar 

  5. 5.

    Kulig, M. et al. Natural course of sensitization to food and inhalant allergens during the first 6 years of life. J. Allergy Clin. Immunol. 103, 1173–1179 (1999).

    CAS  Article  Google Scholar 

  6. 6.

    Martinez, F. D. et al. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N. Engl. J. Med. 332, 133–138 (1995).

    CAS  Article  Google Scholar 

  7. 7.

    Novembre, E. et al. Natural history of “intrinsic” atopic dermatitis. Allergy 56, 452–453 (2001).

    CAS  Article  Google Scholar 

  8. 8.

    Ricci, G. et al. Long-term follow-up of atopic dermatitis: retrospective analysis of related risk factors and association with concomitant allergic diseases. J. Am. Acad. Dermatol. 55, 765–771 (2006).

    Article  Google Scholar 

  9. 9.

    Spergel, J. M. From atopic dermatitis to asthma: the atopic march. Ann. Allergy Asthma Immunol. 105, 99–106 (2010). quiz 7–9, 17.

    CAS  Article  Google Scholar 

  10. 10.

    van der Hulst, A. E., Klip, H. & Brand, P. L. Risk of developing asthma in young children with atopic eczema: a systematic review. J. Allergy Clin. Immunol. 120, 565–569 (2007).

    Article  Google Scholar 

  11. 11.

    Powell, N., Walker, M. M. & Talley, N. J. Gastrointestinal eosinophils in health, disease and functional disorders. Nat. Rev. Gastroenterol. Hepatol. 7, 146–156 (2010).

    Article  Google Scholar 

  12. 12.

    Xenakis, J. J. et al. Resident intestinal eosinophils constitutively express antigen presentation markers and include two phenotypically distinct subsets of eosinophils. Immunology 154, 298–308 (2018).

    CAS  Article  Google Scholar 

  13. 13.

    Carlens, J. et al. Common gamma-chain-dependent signals confer selective survival of eosinophils in the murine small intestine. J. Immunol. 183, 5600–5607 (2009).

    CAS  Article  Google Scholar 

  14. 14.

    Mesnil, C. et al. Lung-resident eosinophils represent a distinct regulatory eosinophil subset. J. Clin. Investig. 126, 3279–3295 (2016).

    Article  Google Scholar 

  15. 15.

    Percopo, C. M. et al. SiglecF+Gr1hi eosinophils are a distinct subpopulation within the lungs of allergen-challenged mice. J. Leukoc. Biol. 101, 321–328 (2017).

    CAS  Article  Google Scholar 

  16. 16.

    Rose, W. A. 2nd, Okragly, A. J., Patel, C. N. & Benschop, R. J. IL-33 released by alum is responsible for early cytokine production and has adjuvant properties. Sci. Rep. 5, 13146 (2015).

    CAS  Article  Google Scholar 

  17. 17.

    Johnston, L. K. & Bryce, P. J. Understanding interleukin 33 and its roles in eosinophil development. Front. Med. 4, 51 (2017).

    Article  Google Scholar 

  18. 18.

    Marichal, T., Mesnil, C. & Bureau, F. Homeostatic eosinophils: characteristics and functions. Front. Med. 4, 101 (2017).

    Article  Google Scholar 

  19. 19.

    Abdala Valencia, H., Loffredo, L. F., Misharin, A. V. & Berdnikovs, S. Phenotypic plasticity and targeting of Siglec-F(high) CD11c(low) eosinophils to the airway in a murine model of asthma. Allergy 71, 267–271 (2016).

    CAS  Article  Google Scholar 

  20. 20.

    McBrien, C. N. & Menzies-Gow, A. The biology of eosinophils and their role in asthma. Front. Med. 4, 93 (2017).

    Article  Google Scholar 

  21. 21.

    Dunican, E. M. et al. Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. J. Clin. Investig. 128, 997–1009 (2018).

    Article  Google Scholar 

  22. 22.

    Hoggatt, A. F., Hoggatt, J., Honerlaw, M. & Pelus, L. M. A spoonful of sugar helps the medicine go down: a novel technique to improve oral gavage in mice. J. Am. Assoc. Lab Anim. Sci. 49, 329–334 (2010).

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Jung, Y. & Rothenberg, M. E. Roles and regulation of gastrointestinal eosinophils in immunity and disease. J. Immunol. 193, 999–1005 (2014).

    CAS  Article  Google Scholar 

  24. 24.

    Mishra, A., Hogan, S. P., Lee, J. J., Foster, P. S. & Rothenberg, M. E. Fundamental signals that regulate eosinophil homing to the gastrointestinal tract. J. Clin. Investig. 103, 1719–1727 (1999).

    CAS  Article  Google Scholar 

  25. 25.

    Bui, L. K., Hayashi, T., Nakashima, T. & Horii, Y. Eosinophilic venulitis in the small intestines in a mouse model of late asthma. Inflammation 34, 499–508 (2011).

    CAS  Article  Google Scholar 

  26. 26.

    Leyva-Castillo, J. M. et al. Mechanical skin injury promotes food anaphylaxis by driving intestinal mast cell expansion. Immunity 50, 1262–75 e4 (2019).

    CAS  Article  Google Scholar 

  27. 27.

    Li, M. Current evidence of epidermal barrier dysfunction and thymic stromal lymphopoietin in the atopic march. Eur. Respir. Rev. 23, 292–298 (2014).

    Article  Google Scholar 

  28. 28.

    Benninger, M. S., Strohl, M., Holy, C. E., Hanick, A. L. & Bryson, P. C. Prevalence of atopic disease in patients with eosinophilic esophagitis. Int. Forum Allergy Rhinol. 7, 757–762 (2017).

    Article  Google Scholar 

  29. 29.

    Jensen, E. T., Martin, C. F., Kappelman, M. D. & Dellon, E. S. Prevalence of eosinophilic gastritis, gastroenteritis, and colitis: estimates from a national administrative database. J. Pediatr. Gastroenterol. Nutr. 62, 36–42 (2016).

    Article  Google Scholar 

  30. 30.

    Lucendo, A. J., Arias, A. & Tenias, J. M. Relation between eosinophilic esophagitis and oral immunotherapy for food allergy: a systematic review with meta-analysis. Ann. Allergy Asthma Immunol. 113, 624–629 (2014).

    Article  Google Scholar 

  31. 31.

    Semancik, E. & Sayej, W. N. Oral immunotherapy for peanut allergy induces eosinophilic esophagitis: three pediatric case reports. Pediatr. Allergy Immunol. 27, 539–541 (2016).

    Article  Google Scholar 

  32. 32.

    Akei, H. S., Mishra, A., Blanchard, C. & Rothenberg, M. E. Epicutaneous antigen exposure primes for experimental eosinophilic esophagitis in mice. Gastroenterology 129, 985–994 (2005).

    CAS  Article  Google Scholar 

  33. 33.

    Venturelli, N. et al. Allergic skin sensitization promotes eosinophilic esophagitis through the IL-33-basophil axis in mice. J. Allergy Clin. Immunol. 138, 1367–80 e5 (2016).

    CAS  Article  Google Scholar 

  34. 34.

    Liu, A. H. et al. National prevalence and risk factors for food allergy and relationship to asthma: results from the National Health and Nutrition Examination Survey 2005–2006. J. Allergy Clin. Immunol. 126, 798–806 e13 (2010).

    Article  Google Scholar 

  35. 35.

    Sampson, H. A. Update on food allergy. J. Allergy Clin. Immunol. 113, 805–819 (2004). quiz 20.

    CAS  Article  Google Scholar 

  36. 36.

    James, J. M. Respiratory manifestations of food allergy. Pediatrics 111(6 Pt 3), 1625–1630 (2003).

    PubMed  Google Scholar 

  37. 37.

    Bivas-Benita, M., Zwier, R., Junginger, H. E. & Borchard, G. Non-invasive pulmonary aerosol delivery in mice by the endotracheal route. Eur. J. Pharm. Biopharm. 61, 214–218 (2005).

    CAS  Article  Google Scholar 

  38. 38.

    Ochkur, S. I. et al. Coexpression of IL-5 and eotaxin-2 in mice creates an eosinophil-dependent model of respiratory inflammation with characteristics of severe asthma. J. Immunol. 178, 7879–7889 (2007).

    CAS  Article  Google Scholar 

Download references


Authors thank Michiko Oyoshi, PhD, Boston Children’s Hospital for technical advice in establishing the skin challenge model. This work was supported by NIH R01AI121186 to L.A.S.

Author information




L.A.S. conceived the project and supervised the work. C.L.O., M.B-.B., J.J.X., and L.A.S. designed experiments. C.L.O., M.B-.B., J.J.X., S.M., E.C., J.F., Q.Y., N.G., R.M., and K.D. performed experiments. C.L.O., M.B.-B., J.J.X., and L.A.S. analyzed data. C.L.O. and L.A.S. wrote the manuscript.

Corresponding author

Correspondence to Lisa A. Spencer.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Olbrich, C.L., Bivas-Benita, M., Xenakis, J.J. et al. Remote allergen exposure elicits eosinophil infiltration into allergen nonexposed mucosal organs and primes for allergic inflammation. Mucosal Immunol 13, 777–787 (2020).

Download citation

Further reading