Neuroimmune buffering reserve at the neurovascular unit: a CLDN5- and microglia-centred view of recurrent peripheral inflammation

Abstract Question Recurrent peripheral inflammatory flares are rarely framed as longitudinal stress tests of the neuroimmune interface. Within the neurovascular unit (NVU), endothelial cells, pericytes, astrocytic endfeet, basement membranes, perivascular cells, and glia jointly regulate blood–brain barrier (BBB) function as a dynamic buffering system rather than a static wall. This Review asks whether recurrent cutaneous flares, used as clinically accessible examples, are associated with altered within-subject recovery kinetics of peripheral endothelial-state signals, and whether these kinetics may inform — at the construct level — a proposed neuroimmune buffering reserve. Boundary This Review advances a hypothesis-driven framework and separates analytical claims from construct-level inference. It does not claim that inflammatory skin disease directly disrupts the BBB, that CLDN5 is a master sensor of the NVU, or that peripheral blood measures establish NVU or microglial state. Circulating soluble endothelial-state markers (VEGF, sICAM-1, sVCAM-1, E-selectin, and VWF) are interpreted as non-BBB-specific indicators of peripheral or systemic endothelial state. CLDN5 is treated as a candidate endothelial locus and readout of dynamic junctional regulation; microglia are proposed state-dependent modulators whose contribution requires convergent central or experimental evidence. Alternative explanations — including autonomic responses, chronic stress and hypothalamic–pituitary–adrenal-axis variation, therapeutic exposures, sleep loss, and cardiometabolic risk — must be considered explicitly. Testability The primary endpoint is the participant-specific recovery time constant τ of the pre-specified soluble endothelial-state panel, estimated with a hierarchical nonlinear mixed-effects model from prospectively scheduled post-peak samples toward each participant’s interflare baseline; response amplitude is a secondary endpoint. Threshold or set-point inference, CLDN5-associated extracellular-vesicle measures, symptoms, and selected central imaging or cerebrospinal-fluid readouts are exploratory and require convergent interpretation. Sampling density, hierarchical modelling details, and pre-specified robustness analyses are given in Box 1. This design does not claim direct BBB rupture or establish BBB-specific endothelial dysfunction.