Exploring the neuroimmune cellular landscape in the skin of subjects with fibromyalgia.

Fibromyalgia (FM) is a chronic disorder involving widespread pain, fatigue, and cognitive impairment. Although its pathogenesis remains uncertain, FM patients exhibit hypersensitivity, reduced intraepidermal nerve fiber density (IENFD), and more recently shown, skin immune dysregulation, possibly manifesting in cutaneous alterations in various cell populations. To characterize the cutaneous cellular landscape in FM, we assessed the sensory profile and skin cell populations across different layers within the same cohort. FM patients, compared to healthy controls (HC), showed lower pain thresholds across multiple body areas, with no differences in thermal detection. While our findings confirm previous reports for reduced PGP9.5+ IENF and increased density in mast cells in FM, we also identified novel changes, particularly in the dermis. We observed elongated thinly myelinated NF200+ fibers and reduced density in non-nerve-associated S100B+ Schwann cells in FM compared to HC. Notably, dermal CD68+ and CD163+ populations were significantly reduced in FM, accompanied by morphological changes. The CD163+ population correlated negatively and significantly against IENFD. These findings suggest that, beyond intraepidermal nerve loss, FM involves broader neuroimmune alterations in the skin, particularly within the dermis, offering new insights into its pathophysiology and establishing a foundation for future studies exploring the functional implications of these changes. SUMMARYAmong the alterations observed in patients with fibromyalgia (FM) are changes in skin innervation and differences in the density of certain immune cell populations. To better characterize FM from an integral perspective, we examined both the sensory profile and the cutaneous cellular landscape of FM patients in comparison with healthy controls (HC). FM patients exhibited lower pain thresholds across multiple body areas, with no differences in thermal detection. Consistent with previous findings, FM skin biopsies revealed reduced intraepidermal nerve fiber density and increased mast cell numbers. Beyond these known alterations, our study identified novel dermal changes, including elongated thinly myelinated NF200+ fibers, reduced density of non-nerve-associated S100B+ Schwann cells, and decreased CD68+ and CD163+ macrophage populations exhibiting morphological alterations. Notably, CD163+ cell density correlated negatively with intraepidermal nerve fiber density, highlighting potential neuroimmune mechanisms underlying the pathophysiology of FM.