Tomer Kagan

Chronic pruritic and cutaneous pain disorders are increasingly recognized as neuroimmune conditions driven by dynamic interactions between immune and sensory systems. While histamine has historically dominated models of mast cell‐mediated itch, accumulating evidence indicates that non‐histaminergic pathways are central to chronic disease. In this review, we synthesize current understanding of mast cell‐neuron communication and propose a unifying framework in which these cells form functional neuroimmune units that sustain itch and pain through bidirectional signalling and feed‐forward amplification. Mast cells release proteases, cytokines, lipid mediators, and neurotrophins that activate and sensitize sensory neurons via receptors including PAR‐2, IL‐31RA, TrkA, and transient receptor potential channels. In parallel, neuron‐derived neuropeptides such as substance P and calcitonin gene‐related peptide drive mast cell activation, notably through MRGPRX2‐dependent mechanisms, reinforcing neurogenic inflammation. These interactions promote peripheral sensitization and structural remodelling of cutaneous innervation, providing a mechanistic basis for persistent symptoms across disorders such as atopic dermatitis, prurigo nodularis, urticaria, neuropathic itch, and chronic pruritus of unknown origin. Importantly, emerging therapies targeting key nodes of this axis ‐ including IL‐4Rα, IL‐31RA, KIT, and Bruton's tyrosine kinase—offer clinical validation of this neuroimmune paradigm. We highlight critical gaps in translating these insights to human disease, including the need for spatially resolved biomarkers and real‐time functional mapping of neuroimmune interactions. Advancing this framework may enable precision‐targeted therapies for chronic itch and skin pain conditions that remain refractory to conventional treatment.

Purpose of Review: Chronic pruritus (CP) is among the most distressing symptoms and has a complex pathophysiology. This review aims to describe the mediators and mechanisms of neuroimmune crosstalk—a term referring the bidirectional interactions between the nervous and immune systems that underly itch pathogenesis and chronicity. Recent Findings: Type 2 cytokines (IL-4, IL-13, IL-31) directly activate pruriceptive neurons, resulting in itch sensation and nerve fiber sensitization via TRPV1/TRPA1, whereas keratinocyte-derived alarmins (TSLP and IL-33) amplify neural activation. Periostin, an emerging downstream mediator, binds integrin αVβ3 on neurons and induces macrophage IL-31 release, representing a link between immune and neural pathways. BNP, another emerging mediator that is co-expressed with IL-31, facilitates itch signaling in the spinal cord and induces keratinocyte production of itch mediators, highlighting its integral role in neuroimmune signaling. Summary: CP arises from a complex interplay between the immune system, sensory neurons, and keratinocytes. The success of therapeutic advances targeting cytokines, neuropeptides, and their receptors in recent years have confirmed the importance of understanding these complex underlying networks.

The delivery of genetically encoded fluorescent sensors via adeno-associated viral vectors (AAVs) enables the quantification of biological analytes with high spatiotemporal resolution in living animals. In this study, we expose an unreported problem of the approach, in which the presence of repeated subsequences in the sensor’s DNA sequence triggers recombination during AAV production. In the case of Förster Resonance Energy Transfer (FRET) sensors, recombination leads to a mixture of fluorescent products, severely compromising in vivo functionality. To counter this phenomenon, we introduce Abundance-Biased Codon Diversification (ABCD), a modification of a previously reported codon diversification method that prevents recombination without sacrificing codon optimization for a target organism. We demonstrate that ABCD greatly facilitates in vivo studies by restoring the functionality of FRET sensors and advanced inducible expression systems delivered via AAV vectors. Our approach offers a robust solution to a previously overlooked challenge, significantly expanding the range of future applications in quantitative imaging and genetic manipulation in living animals using AAV-mediated strategies.