Crystal Sensing and Neurogenic Inflammation in Gout: A Proposed Sensory Neuroimmune Framework for Flare Pain

Gout is a crystal-induced inflammatory arthritis caused by deposition of monosodium urate (MSU) crystals. The established mechanistic model centers on innate immune recognition of MSU crystals, NLRP3 inflammasome activation, caspase-1-dependent interleukin-1β (IL-1β) maturation and neutrophil-rich synovitis. Although this framework remains fundamental, it does not fully account for the intensity of flare pain or its close coupling with vascular and inflammatory responses, while the mechanisms underlying flare recurrence remain incompletely understood. Increasing evidence indicates that nociceptive sensory neurons can actively regulate local inflammation rather than merely transmit pain. This article is a mechanistic narrative review and does not follow PRISMA-based systematic-review methodology. Relevant evidence was identified through structured searches of MEDLINE via PubMed and the Web of Science Core Collection, supplemented by backward and forward citation tracking. Current gout-specific experimental evidence supports two complementary mechanistic segments: TRPV4-dependent macrophage crystal sensing linked to NLRP3-IL-1β activation, and CXCL5-neuronal CXCR2-TRPA1 signaling linking inflammatory cues to nociceptor activation and vascular amplification. However, direct human evidence remains limited and compartment-specific, and a continuous macrophage-nociceptor-vascular-neutrophil circuit has not been demonstrated within the human gout joint. We therefore propose this sensory neuroimmune framework as a testable, evidence-integrating model rather than a fully validated linear pathway. Local neuroimmune priming, persistent sensory sensitization and possible dissociation between inflammatory and sensory resolution remain testable hypotheses requiring longitudinal human validation. This framework extends rather than replaces the MSU-NLRP3-IL-1β paradigm and identifies priorities for future mechanistic and translational investigation.