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Basophils getting on your nerves? Itching for clarity on flares in atopic dermatitis

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Science Immunology  05 Feb 2021:
Vol. 6, Issue 56, eabg8047
DOI: 10.1126/sciimmunol.abg8047

Abstract

Flares of acute itch in the setting of atopic dermatitis may engage a novel neuroimmune axis that includes basophils, LTC4, and sensory neurons.

Atopic dermatitis (AD) is an inflammatory skin disorder, and patients suffer from both chronic inflammation and acute “flare” episodes. Recent work has demonstrated key roles for neuroimmune mechanisms underlying chronic itch. Here, Wang et al. tackle the etiology of acute itch flares in AD. They began by investigating how placebo-treated moderate and severe AD patients in clinical trials fared on a fine time scale and found that nearly half had an acute itch episode over a two-month period. AD patients with specific anti-allergen IgE were more likely to have had acute itch episodes, so they used AD mouse models to test potential mechanisms linking IgE and acute itch flares. Their mouse AD model involved treating ear skin simultaneously with an allergen (OVA) and an irritant (MC903) over 10 days, yielding chronic itch. Challenge with intradermal (i.d.) injection of OVA then yielded acute itch flares. The acute itch episodes in the setting of AD were IgE, but not mast cell (MC), dependent. Basophils were the logical focus because they also bear the relevant IgE receptor and had an altered activation state in human AD patients. Targeted activation of basophils via a chemogenetic approach elicited itch flares. Depleting basophils from the AD model reduced acute itch. Factors released by basophils upon challenge in their AD model yielded itch and activated sensory neurons. Mouse peripheral blood basophils, when compared to tissue resident MC, showed evidence of increased leukotriene biosynthesis. Blockade of 5-LOX via multiple strategies ameliorated acute itch. Two-photon imaging demonstrated basophils in sensitized skin, with altered basophil morphology and motion after challenge, with repeated contacts between basophils and sensory neurons. Finally, they linked the acute flare episodes in the mouse AD model to leukotriene C4 (LTC4) release from basophils, signaling via CysLTR2, and reliance on TRPV1 and TRPA1 in sensory neurons to promote itch.

This paper delineates a novel neuroimmune axis in itch and novel therapeutic targets in AD, some with medications already approved for human use. This axis remains to be tested in human AD (e.g., anti-5-LO) and will require a nuanced consideration of acute-on-chronic symptoms. This continued deepening of our understanding of neuroimmune pathways in AD (and broadly) will hopefully improve chronic inflammation, acute exacerbations, and quality of life for our AD patients via improved future therapeutics.

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