Jing Feng

Visceral pain in ulcerative colitis is conventionally attributed to inflammatory cascades, though whether immune cells directly transduce mechanical cues into nociceptive signals remains unclear. Here, we show that the mechanosensitive channel Piezo1 in tissue-resident CX3CR1 ⁺ macrophages directly drives colitis-associated visceral hypersensitivity. Piezo1 triggered calcium influx and nuclear factor κB nuclear translocation that occupied the Ngf promoter to induce nerve growth factor (NGF) synthesis. This macrophage-derived NGF remodeled and sensitized the peripheral terminals of TRPV1 ⁺ nociceptive afferents in neuroimmune units. Using a minimally inflammatory intracolonic zymosan model, we found that this Piezo1-NGF-TrkA axis functions as a direct mechanosensory relay largely independent of cytokine cascades. Genetic deletion of Piezo1 or Ngf in resident macrophages, or Ntrk1 in TRPV1 ⁺ neurons, abolished visceral hyperalgesia in both inflammatory and noninflammatory models. These findings reveal tissue-resident macrophages as autonomous mechanical sensors that establish a direct, parallel pain transmission pathway to sensory nerves during disease.

Occipital neuralgia (ON) is a refractory chronic headache disorder characterized by paroxysmal shooting or stabbing pain in the posterior scalp, innervated by occipital nerves that originate from C2 and C3 dorsal root ganglion (DRG) neurons. Limited access to human DRG samples has impeded the understanding of the cellular and molecular mechanisms and the development of effective treatments for ON. We innovatively employed percutaneous full-endoscopic C2 ganglionectomy and subsequently performed single-nucleus RNA-sequencing (snRNA-seq) on C2 DRG from both ON patients and healthy controls. Somatostatin-expressing (SST⁺) neurons were selectively downregulated in patients with ON. Behavioral studies demonstrated that ablation of SST⁺ neurons induced pain, while optogenetic or chemogenetic activation of these neurons alleviated acute and chronic pain in mice. Altogether, this study provides new insights into the mechanisms underlying ON, revealing potential therapeutic targets for pain management.

Cutaneous bacterial infections frequently elicit severe pruritus, prominently featuring alloknesis, a pathological state where innocuous touch provokes intense itch. However, the peripheral mechanisms translating microbial cues into touch-evoked pruritus remain unresolved. Here, we establish an epicutaneous Pseudomonas aeruginosa infection model that robustly isolates mechanical alloknesis from spontaneous scratching. We identify bacterial flagellin as the critical virulence factor driving this specific sensory modality via Toll-like receptor 5 (TLR5) activation exclusively within Calb1 ⁺ Aβ rapidly adapting low-threshold mechanoreceptors (RA-LTMRs). Mechanistically, pathogen-driven TLR5 signaling depletes intracellular PIP2, which suppresses KCNQ4-mediated M-currents and dismantles the biophysical brake on LTMR excitability. Our findings define a distinct microbial-neuronal axis that directly converts tactile stimuli into itch at the peripheral entry point, providing an infection-based framework for dissecting pathogen-sensory neuron interactions and uncovering precise therapeutic targets for chronic, touch-evoked pruritus. TEASER A bacterial flagellin-sensing touch neuron pathway converts innocuous touch into itch during skin infection.

Gouty arthritis is an autoinflammatory joint disease caused by the deposition of monosodium urate crystals, which activate innate immune responses and elicit acute episodes of joint pain and inflammation. Although macrophages are key players in recognizing monosodium urate (MSU) crystals and initiating the inflammatory cascade, the specific contribution of tissue-resident macrophages and their mechanosensory machinery remains unclear. Here, we identify the mechanosensitive ion channel PIEZO1 as a critical mediator of inflammation and pain in MSU-induced acute gout. We show that synovial CX3CR1⁺ tissue-resident macrophages are enriched and activated in both patient samples and a murine model of gout. PIEZO1 is highly expressed in these cells and responds to mechanical stress with calcium influx, which is further amplified in MSU-treated joints. Pharmacological inhibition or genetic ablation of PIEZO1 in CX3CR1⁺ macrophages significantly attenuated joint swelling, inflammatory cytokine expression, mechanical hypersensitivity, and motor dysfunction. In contrast, Piezo1 deletion in CCR2⁺ monocytes, MRP8⁺ neutrophils, or Col1a2⁺ fibroblasts did not affect gout-associated symptoms, indicating a non-redundant role for resident macrophage-expressed PIEZO1. These findings define a PIEZO1-dependent mechanotransduction pathway in tissue-resident macrophages that drives gout-related inflammation and nociception and suggest that targeting PIEZO1 may offer therapeutic benefit in acute gout flares.

The lymphatic system, traditionally regarded as a unidirectional conduit for interstitial fluid and immune cell transport, has recently been redefined through the discovery of lymphatic networks along the spinal axis. These spinal lymphatic vessels, encompassing the spinal cord, vertebral bones, and intervertebral discs, challenge long-standing anatomical dogmas and introduce new perspectives on the interplay between the central nervous system (CNS) and the vertebral column. This review systematically summarizes the distribution and dual functions of the spinal lymphatic system in regulating cerebrospinal fluid drainage, maintaining tissue homeostasis, and mediating immune responses. Furthermore, we highlight emerging evidence linking spinal lymphatic dysfunction to spinal pathologies, neurological disorders, and vertebral degeneration. Based on these findings, we propose that the spinal lymphatic system constitutes a previously underappreciated pathway integrating spinal cord and vertebral physiology, with potential implications for both disease progression and therapeutic intervention. While research on the cranial lymphatic system has rapidly advanced, the spinal lymphatic system remains comparatively underexplored. We hope this review will catalyze further investigation into spinal lymphatic biology and inform the development of novel therapeutic strategies targeting spinal and neurological diseases.

Platelets are traditionally recognized for their roles in hemostasis, but their involvement as active immune modulators in cutaneous neuroimmune signaling remains poorly understood. In this study, we integrated multi-modal genetic and pharmacological strategies to investigate the functional contribution of platelets to skin inflammation and chronic itch. Optogenetic activation of platelets was sufficient to elicit localized skin inflammation, erythema, and robust pruritus, with transcriptomic profiling of lesions showing strong concordance with the clinical signatures of atopic dermatitis (AD). In experimental AD models, platelet depletion markedly reduced scratching behavior, inflammatory cell infiltration, and C-fiber excitability, whereas platelet activation exacerbated these phenotypes. Mechanistically, activated platelets release serotonin [5-hydroxytryptamine (5-HT)], which compromises vascular integrity and facilitates platelet extravasation into the dermis. This “neuroimmune hub” promotes macrophage recruitment and sensitizes TRPV1 ⁺ pruriceptors. Transcriptomic analysis revealed that platelet-derived 5-HT drives these processes via HTR2B and HTR7 signaling. Specifically, genetic ablation of HTR2B in TRPV1 ⁺ neurons selectively impaired itch transmission. Furthermore, re-analysis of clinical datasets confirmed the enrichment of HTR2B and HTR7 in skin macrophage populations during inflammation. Systemic administration of HTR antagonists or the anti-platelet agent clopidogrel markedly attenuated both inflammation and pruritus across multiple models. Our findings identify the platelet–immune–neuron axis as a key driver of cutaneous dysfunction and a promising therapeutic target for chronic inflammatory skin disorders.

Keratinocytes actively contribute to somatosensory signaling in chronic skin diseases, yet the mechanotransduction mechanisms involved in atopic dermatitis (AD)-associated itch remain unclear. Here we identify keratinocyte-expressed mechanosensitive ion channel Piezo2 as a critical driver of chronic itch in AD. While Piezo1 was constitutively expressed and dispensable for chronic itch in the MC903-induced AD model, Piezo2 expression was markedly upregulated in keratinocytes of lesional AD skin. Keratinocyte-specific Piezo2 deletion attenuated spontaneous scratching and spontaneous C fiber activity, while having minimal impact on skin inflammation. Mechanistically, Piezo2 suppressed the neurorepulsive factor Semaphorin 3A (Sema3a), a key regulator of sensory nerve architecture. Loss of Piezo2 restored Sema3a expression in the epidermis, reduced nerve fiber branching, and dampened C fiber hyperexcitability. Furthermore, keratinocyte-specific ablation of Sema3a exacerbated AD-related itch and nerve fiber outgrowth. These findings establish a non-neuronal epithelial mechanism wherein keratinocyte Piezo2 modulates sensory nerve remodeling and pruritus in chronic skin inflammation, offering potential targets for therapeutic intervention.

Hematopoietic stem cells (HSCs) rely on precisely controlled proteostasis to sustain lifelong self-renewal, yet whether intrinsic proteostatic characteristics can prospectively define functional diversity within the HSC pool remains unknown. In this study, we developed a dual-fluorescence reporter system to visualize endoplasmic reticulum-associated degradation (ERAD) activity in vivo and discovered that ERAD activity can prospectively predicts the long-term reconstitution potential of HSCs. Remarkably, ERAD states were maintained through self-renewal, revealing an inheritable “proteostatic memory” within the HSC pool. Transcriptomic and functional analyses identified SOCS2 as a key regulator of this process: SOCS2 inhibits JAK2 signaling to sustain ERAD activity, whereas hyperactive JAK2 interacts with the ERAD E3 ligase Hrd1 and suppresses VCP-mediated misfolded substrate. These findings define a SOCS2-JAK2-ERAD axis that connects cytokine signaling to intrinsic proteostasis remodeling, establishing ERAD activity as a predictive and heritable marker of HSC function and providing a conceptual framework for understanding hematopoietic stem cell heterogeneity.