Affective tactile stimulation ameliorates chronic pain and comorbid anxiety by modulating hippocampal CA1 oscillations and functional connectivity.

Chronic inflammation contributes not only to autoimmune diseases such as rheumatoid arthritis (RA), but also to the onset and progression of a wide range of disorders, including neurodegenerative, neuropsychiatric, and metabolic diseases []. A major challenge for early diagnosis is that disease-associated inflammatory events often arise as spatially restricted, low-abundance, and transient changes before overt clinical manifestations. In this article, we refer to such early localized events as micro-inflammation, thereby distinguishing them from generalized systemic low-grade inflammation. From the standpoint of nano-enabled diagnostics, these features make chronic inflammation a particularly difficult target, because conventional assays and imaging methods often fail to detect inflammatory processes until they have progressed to tissue-damaging states. Although chronic inflammation has traditionally been attributed mainly to dysregulated immune-cell networks initiated by T cells, including autoreactive populations [, ], increasing evidence indicates that its persistence and tissue specificity are critically shaped by non-immune cells, including tissue-resident cells, vascular endothelial cells, and fibroblasts [–]. One mechanistic framework for this concept is the IL-6 amplifier, a positive-feedback inflammatory circuit in non-immune cells driven by the simultaneous activation of NF-κB and IL-6–STAT3 signaling [–]. Activation of this pathway promotes sustained production of cytokines and chemokines, thereby converting subtle local perturbations into self-reinforcing inflammatory niches that recruit immune cells and amplify tissue inflammation. In this sense, the IL-6 amplifier provides a useful model for understanding how micro-inflammatory seeds may arise and persist before overt chronic inflammatory disease becomes clinically apparent. At the same time, the molecular detection of these early events remains technically challenging, and methods capable of sensitively capturing IL-6 amplifier-associated changes at presymptomatic stages are still limited. The central nervous system (CNS) offers a particularly informative setting in which to study the spatial organization of micro-inflammation. Under physiological conditions, the blood-brain barrier (BBB), which is formed by endothelial cells together with supporting cellular and matrix components, tightly regulates the trafficking of immune cells and macromolecules and thereby preserves CNS homeostasis [, ]. Nevertheless, under defined pathological conditions, blood-derived immune cells can enter the CNS and contribute either to host defense or to neuroinflammatory and autoimmune disease. Multiple sclerosis (MS) is a prototypical autoimmune disease of the CNS in which autoreactive CD4 + T cells recognizing myelin antigens infiltrate the CNS and induce demyelination and neurological dysfunction [, ]. Studies using experimental autoimmune encephalomyelitis (EAE) led to the identification of the gateway reflex, a neuroimmune mechanism in which specific neural inputs induce discrete vascular “gates” that permit selective entry of blood immune cells, including autoreactive T cells, into the CNS. Subsequent work has shown that diverse stimuli, including gravity, electrical stimulation, pain, stress, light exposure, and joint inflammation, can induce gate formation at distinct vascular sites [–]. These findings suggest that micro-inflammation is not only molecularly amplified but also spatially regulated by neural activity. However, most of the supporting evidence for these mechanisms has been obtained in animal models, and the extent to which analogous site-specific vascular inflammatory programs can be detected or monitored in humans remains an important translational question.