Figure 4.

Pain-gateway reflex. Pain-induced sensory stimulation (1, 2) induces the activation of the anterior cingulate cortex (ACC), a pain-processing region in the brain (3), which leads to the activation of specific sympathetic nerves (4), followed by norepinephrine (NE) secretion around the ventral blood vessels of the spinal cords (5). Because major histocompatibility complex (MHC) class 2^HiCD11b⁺ monocytes are most abundant in the fifth lumbar spinal cord (L5), the L5 region is mainly affected after pain induction. NE secreted around the ventral blood vessels stimulates the production of chemokine CX3CL1 from MHC class 2^HiCD11b⁺ monocytes. Because MHC class 2^HiCD11b⁺ monocytes express CX3CL1 receptor CX3CR1, a positive loop is formed to recruit more of them (6). MHC class 2^HiCD11b⁺ monocytes have an ability to antigen presentation to pathogenic CD4⁺ T cells, leading to their invasion (7) and subsequently cause disease relapse.