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Sensory immune and metabolic interactions in ischemic stroke and inflammatory diseases inform emerging therapeutic strategies

Year: 2026

Type: article

Abstract: Sensory afferents are increasingly recognized as active participants in tissue homeostasis through interactions with vascular, immune, and parenchymal cells. In ischemic stroke, however, these pathways operate within a broader multicellular pathophysiology that also includes energy failure, excitotoxicity, oxidative stress, blood-brain barrier disruption, systemic immune responses, and multiple regulated cell-death programs [ 1 , 2 , 3 , 4 ]. This review examines how sensory receptors and neuropeptides may contribute to neuroimmune and metabolic remodeling in ischemic and inflammatory disease. TRPV1 is discussed as one component of a wider transient receptor potential channel network rather than as an exclusive upstream regulator [ 2 , 5 ]. Substance P (SP) has comparatively direct preclinical support as a mediator of neurogenic inflammation and edema after cerebral ischemia, whereas calcitonin gene-related peptide (CGRP) has context-dependent vascular and immune effects [ 6 , 7 ]. CGRP-targeted monoclonal antibodies and receptor antagonists are clinically established for migraine, but they have not been validated as stroke treatments; notably, CGRP receptor antagonism worsened ischemic outcomes in a mouse model by impairing collateral perfusion [ 8 , 9 , 10 ]. We further review mitochondrial dysfunction, SIRT1/PGC-1α signaling, lipid peroxidation, and ferroptosis as intersecting metabolic processes, while emphasizing that direct causal links from sensory signaling to these pathways in human stroke remain incompletely established [ 11 , 12 , 13 , 14 ]. The sensory-immune-metabolic framework is best viewed as a hypothesis-generating integrative model embedded within the broader neurovascular unit response to ischemia rather than as a dominant disease driver. Physical neuromodulation and ferroptosis-modulating compounds remain investigational for mechanism-specific stroke prevention. Future work should prioritize causal validation, receptor redundancy, dose and timing effects, translational pharmacology, and biomarker-stratified clinical studies before axis-directed interventions can be considered for routine stroke care.

Source: Discover Neuroscience

DOI: 10.1186/s13064-026-00340-y