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Adding intestinal insult to skin injury

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Science Immunology  05 Jul 2019:
Vol. 4, Issue 37, eaat0809
DOI: 10.1126/sciimmunol.aat0809

Abstract

Mechanical skin injury promotes food allergy.

Severe food allergies, which can cause life-threatening anaphylactic reactions, have been on the rise. Atopic dermatitis (AD), a chronic pruritic inflammatory skin disease, remains one of the risk factors that predispose individuals to food allergies, but the mechanisms underlying this process has been elusive. Itching, scratching, and the consequent skin injury are major features of AD. Using tape stripping to model the mechanical skin injury of AD, Geha and colleagues demonstrate that skin injury induces a cytokine relay between skin keratinocytes, intestinal epithelial tuft cells, and intestinal group 2 innate lymphoid cells (ILC2s) that results in an expansion of intestinal mast cells and promotes anaphylactic responses to oral antigen challenge. Mechanistically, skin injury causes keratinocytes to release interleukin-33 (IL-33) into systemic circulation, which activates intestinal ILC2s to release IL-13 and promote expansion of and IL-25 production by intestinal tuft cells. This creates a feedforward loop that culminates in mast cell expansion induced by ILC2s production of IL-4 and IL-13. Mast cell expansion in tape-stripped mice led to enhanced intestinal permeability and increased severity of anaphylactic responses to orally administered antigens compared to control mice. The authors used an impressive battery of genetically engineered mice to conditionally knockout genes of interest to arrive at this pathway. Notably, they show that keratinocyte-specific deletion of IL-33, intestinal epithelial cell–specific deletion of IL-25, ILC2-specific deletion of IL-4 and IL-13 or receptors for IL-25 or IL-33, and mast cell–specific deletion of IL-4/IL-13 receptor all result in abrogation of mast cell expansion induced by tape stripping. Extending these findings to humans, the authors found that intestinal biopsies from AD patients harbor more mast cells than those from individuals without AD, suggesting that a similar process occurs in patients with skin inflammation. Although further studies will be needed to test the clinical impact of the targets uncovered in this study, this work provides important mechanistic insights linking AD with food allergy.

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