Figure 1.

Neurogenic inflammation mechanism of action in Rheumatoid arthritis (RA). The mechanism of action of neuroinflammation in RA consists of: (1) activation and invasion of inflammatory synovial cells (T cells, B cells, macrophages, plasma cells, and dendritic cells) leading to peripheral sensitization and local inflammatory reaction that (2) sensitizes peripheral small diameter fibers (A, B, and C fibers), hence generating dorsal root reflexes. (3) Peripheral nerve endings and the central nerve endings originating from the dorsal root ganglion release substance P (SP), calcitonin gene-related peptide (CGRP), and glutamate that peripherally act on post-capillary venules, rendering them leaky and resulting in plasma extravasation and vasodilation, while, centrally, they trigger neurogenic inflammation. Therefore, this integrated inflammatory network (4) enhances the release of inflammatory cytokines nerve growth factor beta (NGF-β), interleukin (IL)-1, IL-6, IL-17, and tumor necrosis factor alpha (TNF-α) (as indicated by the red arrows) and (5) activates microglial cells in the dorsal horn of the spinal cord.