Microglia, the resident immune cells of the central nervous system, play multifaceted roles in both health and disease. During development, they regulate neurogenesis and refine neural circuits through synaptic pruning. In adulthood, microglia maintain homeostasis and dynamically respond to pathological insults, where they contribute to responding to neuroinflammatory challenges. This review summarizes microglial contributions to neurodevelopment and also outlines their function across various neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, highlighting both protective and detrimental effects. Finally, recent advances in microglial-targeted therapies and lifestyle-based interventions are highlighted, underscoring the translational potential of modulating microglial states. Elucidating the dual roles of microglia in development and disease could guide the design of therapeutic strategies aimed at enhancing neuroprotection while minimizing neurotoxicity.

Chronic itch, affecting 8–10% of the global population, is a debilitating condition linked to dermatoses, systemic diseases, and neurological disorders, with limited therapeutic efficacy due to unclear central mechanisms. Spinal microglia, central nervous system-resident immune cells, regulate neuroinflammation and synaptic plasticity in chronic pain and neurodegeneration, but their role in chronic itch remains unknown. This study investigated the role of spinal microglia in chronic itch. Using an allergic contact dermatitis (ACD) mouse chronic itch model, we found robust microglial activation, accompanied by c-Fos-positive neuronal activation, in the spinal dorsal horn of a chronic itch model. Pharmacological inhibition (minocycline) or genetic ablation of microglia significantly reduced mechanical itch hypersensitivity and spontaneous scratching, alongside decreased microglial/neuronal activation. Morphological and molecular analyses revealed downregulated antioxidants (glutathione peroxidase 4 [GPX4], superoxide dismutase [SOD], glutathione [GSH],) and upregulated lipid peroxidation (malondialdehyde [MDA], acyl-CoA synthetase long-chain family member 4 [ACSL4]) in the spinal cord, indicating ferroptosis. Intrathecal liproxstatin-1 (ferroptosis inhibitor) alleviated itch behaviors and restored GPX4, SOD, GSH and MDA level, without affecting microglial activation. Our findings demonstrate that spinal microglia promote chronic itch by triggering ferroptosis in spinal dorsal horn. These findings provide the first evidence of microglia-ferroptosis crosstalk in chronic itch, providing a mechanistic basis for targeting glial activity or ferroptosis to develop novel therapies.

Chronic itch, a devastating dermatological disorder, lacks targeted therapies due to incomplete understanding of its neural circuitry. Building on seminal studies that identified neuropeptide Y (NPY) inhibitory interneurons and their downstream urocortin 3-positive (Ucn3 ⁺ )/Y1R-expressing neurons, calcitonin receptor-like receptor-positive (Calcrl ⁺ ) neurons, identified as spinal projection neurons, have been proposed to contribute to mechanical itch signaling, though their underlying mechanistic role remains undefined. In the present study, using chemogenetic manipulation, behavioral tests, morphological assays and electrophysiological approaches in allergic contact dermatitis, atopic dermatitis and Psoriasis chronic itch models, we elucidates the role of spinal Calcrl ⁺ neurons in mechanical itch pathophysiology. We report that: (1) Chemogenetic activation of spinal Calcrl ⁺ neurons induces enhanced mechanical itch sensitization and increased spontaneous scratching behaviors in naïve mice; (2) Chemogenetic inhibition of spinal Calcrl ⁺ neurons alleviates mechanical itch sensitization and spontaneous scratching behaviors in chronic itch models; (3) Chronic itch enhances intrinsic excitability of Calcrl+ neurons in chronic itch model; (4) Aβ-fiber-evoked synaptic excitation of Calcrl+ neurons is significantly amplified in chronic itch, accompanied by reduced inhibitory input. Our study elucidates a pathological synaptic plasticity mechanism in chronic itch, wherein spinal Calcrl+ neurons undergo hyperexcitability, enhanced Aβ-fiber-evoked excitatory transmission and reduced inhibitory input. These findings establish a spinal Calcrl-dependent circuit as a critical driver of mechanical itch sensitization, providing actionable targets for disrupting maladaptive itch circuits in dermatological disorders.