Regulation of peripheral inflammation by the central nervous system

Abstract

In inflammatory disorders such as rheumatoid arthritis, cytokines and danger signals are sensed by the central nervous system, which adapts behavior and physiologic responses during systemic stress. The central nervous system can also signal the periphery to modulate inflammation through efferent hormonal and neuronal pathways. The brain and spinal cord are involved in this bidirectional interaction. A variety of neuronal pathways that modulate synovial inflammation have been implicated, including the sympathetic and the parasympathetic branches of the autonomic system. Another mechanism, the dorsal root reflex, involves antidromic signaling along somatic afferent fibers that influences joint inflammation by releasing neuropeptides and other neuromediators in the periphery. Some of the neurotransmitters and neuroreceptors involved have been identified in preclinical models and represent novel targets for the treatment of rheumatic diseases.

Fig. 1

Schematic description of the main neuronal pathways involved in the regulation of synovial inflammation. Vagal nerve firing leads to acetylcholine (ACh) release in the periphery. ACh is an agonist for the α7 nicotinic receptor on macrophages and fibroblast-like synoviocytes (FLS) and decreases the release of cytokines and chemokines. Vagal fibers are detected in peripheral organs such as the bronchi (dashed lines), but not in the synovium. In organs not directly innervated by the vagus, such as the spleen or the joints, vagal stimulation is postulated to stimulate autonomic fibers to release norepinephrine (NE), which in turn triggers ACh release via a non-neuronal cholinergic system. The peripheral increase in ACh is sensed by the nicotinic α7 receptor, which downregulates the release of proinflammatory cytokines. Central and intrathecal administration of p38 inhibitors stimulates the vagal nerve and decreases synovial inflammation. In rheumatoid arthritis, loss of noradrenergic fibers inhibits the anti-inflammatory action of the sympathetic system (β2 receptors) and the vagal system. Stimulation of peripheral C-afferent fibers releases excitatory amino acid (eg, glutamate) in the spinal cord, which then binds to N-methyl-D-aspartate (NMDA) receptors to decrease adenosine release by afferent fibers. Adenosine has an anti-inflammatory effect in the periphery by binding to A2 receptors on neutrophils and FLS and on central A1 receptors that inhibit NMDA receptor activation. AG autonomic ganglion; IL interleukin; Mφ macrophage; PMN polymorphonuclear leukocyte; Pp38 phospho-p38 mitogen-activated protein kinase; SB i. t. intrathecal SB203580 (p38 inhibitor); TNF tumor necrosis factor