Journal Club 26.02.02

Neuronal pentraxin 2 in peripheral sensory neurons drives chronic itch through potentiation of the interleukin-31/interleukin-31 receptor pathway in atopic dermatitis

Xue-Qiang Bai ^{a b 1}, Bing-Xin Wu ^{a 1}, Ji-An Wang ^{c 1}, Cheng He ^a, Yong-Liang Shen ^d, Xiao Wei ^a, Yu-Qi Zhang ^a, Xue-Wen Chen ^c, Rong Sun ^a, Qun-Feng Gui ^d, Juan Wang ^a,  Zhi-Jun Zhang ^{a e}

Keywords
Pruritus; NPTX2; Interleukin-31; Trigeminal ganglion; Atopic dermatitis

Abstract

Atopic dermatitis (AD) is one of the most prevalent chronic inflammatory skin conditions, primarily characterized by intense itching that leads to scratching and presents a challenging clinical issue with incompletely understood mechanisms. Neuronal pentraxin 2 (NPTX2) is associated with neurodevelopment, synaptic plasticity, and neuroinflammation in the central nervous system. In this study, we aimed to thoroughly investigate the peripheral role of NPTX2 in mediating chronic itch in AD. Real-time polymerase chain reaction (PCR), immunohistochemistry, ELISA assays, western blot, and small interfering RNA (siRNA) intervention were performed to explore the peripheral role of NPTX2 in an AD model. We demonstrated that NPTX2 was selectively upregulated in small- and medium-sized trigeminal ganglion (TG) neurons in the MC903-induced AD model, and was transported to peripheral nerve terminals. Importantly, protein expression of NPTX2 was significantly elevated in the skin nerves of patients with AD. Notably, NPTX2 administration alone, intradermally, provoked moderate scratching behavior in mice. However, Nptx2 and neuronal pentraxin receptor (NPTXR) siRNA intra-TG injection significantly attenuated scratching behaviors in AD mice. Critically, NPTXR, its cognate receptor, was specifically localized to pruriceptive calcitonin gene–related peptide-positive neurons (CGRP⁺) and isolectin B4 (IB4⁺) neuronal subsets. Mechanistically, NPTX2 synergizes with interleukin-31 (IL-31), a well-known pruritic cytokine in AD, to potentiate phosphorylated-extracellular signal-regulated kinase (p-ERK) signaling in primary sensory neurons. PD98059, the inhibitor of p-ERK, significantly alleviated the scratching induced by the combination of NPTX2 and IL-31. Additionally, PD98059 also significantly reduced the upregulation and release of NPTX2 caused by IL-31 stimulation. Our results offer a new understanding of the molecular mechanisms underlying chronic pruritus in the MC903-induced AD model, highlighting NPTX2-dependent signaling as a key therapeutic strategy for refractory itch disorders.

https://doi.org/10.1016/j.intimp.2026.116223