Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch

Abstract

SUMMARY Mammals have evolved neurophysiologic reflexes such as coughing and scratching to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also associated with chronic inflammatory diseases such as asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.

Molecular and Functional Neuroscience in Immunity

“…In addition to sensing immune molecules and pathogens, afferent neurons actively modulate immune responses and inflammation, as demonstrated in experimental IBD (46), arthritis (48), asthma (60), skin inflammation and chronic itch (61, 62), and bacterial infection (3, 42). Sensory neurons release substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), and other molecules interacting with the endothelium, neutrophils, macrophages, and other immune cells in the vicinity of axonal terminals (3, 42, 63) (Figure 2).…”

Neuroimmune interactions in chronic itch of atopic dermatitis

“…4,34,35 Some AD-associated cytokines, IL-31 and thymic stromal lymphopoietin (TSLP), can directly promote itch via activation of pruritoceptive TRPV1+ TRPA1+ neurons that express their receptors. 38 Cytokine-to-neuron signalling by IL-31, TSLP and IL-4all present in skin during AD flaresmay explain the rapid benefit of JAK1/2 and IL-4Ra inhibition vs. chronic pruritus and pruritus in AD. 38 Cytokine-to-neuron signalling by IL-31, TSLP and IL-4all present in skin during AD flaresmay explain the rapid benefit of JAK1/2 and IL-4Ra inhibition vs. chronic pruritus and pruritus in AD.…”

“…36,37 In addition, IL-4 may potentiate itch by sensitizing itch-sensory neurons to direct pruritogens, such as histamine and IL-31. [36][37][38][39][40][41] Figure 2 Crosstalk between nerves, immune cells and keratinocytes fuel pruritus in AD lesional skin. [36][37][38][39][40][41] Figure 2 Crosstalk between nerves, immune cells and keratinocytes fuel pruritus in AD lesional skin.…”

The IL‐13–OVOL1–FLG axis in atopic dermatitis

“…Hence, different types of oral and topical JAK inhibitors are significantly therapeutic against AD . As IL‐4R α is expressed on sensory nerves, and its activation is involved in the itch sensation, the administration of a JAK inhibitor reduces itch intensity …”