Afferent Vagus Nerve Stimulation Activates Brain Locus Coeruleus and Improves Experimental Joint Inflammation

Vagus Nerve Stimulation Joint Inflammation
Vagus Nerve Stimulation – Joint Inflammation

A recent study published in the Brain, Behavior, and Immunity  journal indicates, for the first time, that stimulation of vagal afferents or specific brain areas can modulate joint inflammation. This new central pathway involves sympathetic nervous system activation and local stimulation of synovial β-adrenoceptors.

Articular inflammation is a major hallmark and pathological burden in clinical and experimental arthropathies such as rheumatoid arthritis. Articular inflammation causes joint pain, edema, stiffness as well as loss of functionality due to the infiltration of leukocytes into the synovial cavity and the production of inflammatory cytokines such as tumor necrosis factor (TNF).

The regulation of immunity by the nervous system has been widely studied, and the discovery of these mechanisms helped to design novel therapeutic strategies for inflammatory diseases. Among these neuroimmune pathways, vagus nerve stimulation has received received considerable attention due to its potential to control inflammation and improve survival in experimental models of infectious and inflammatory disorders

Vagus nerve stimulation (VNS) is a well-known procedure that limits inflammation and improves survival in animal models of immune/inflammatory diseases & conditions such as arthritis and sepsis. The proposed mechanism involves an efferent (peripheral) connection between the vagus nerve and the immune system, where the release of acetylcholine inhibits macrophage production of tumor necrosis factor (TNF)-α by activating α7-nicotinic acetylcholine (α7 nACh) receptors. This neuro-immune system’s connection is known as the ‘cholinergic anti-inflammatory pathway’.

However, several groups have indicated that afferent vagal stimulation also can inhibit inflammation, but by unknown brain and spinal cord axis pathway. It seems that ‘‘peripheral (afferent)-central-peripheral (efferent)” neuronal arcs are important physiological mechanisms modulating the immune system in diverse conditions. Moreover, other studies showed that efferent VNS in α7 nACh KO mice still reduce systemic inflammation, suggesting other immunomodulatory mechanisms besides the cholinergic pathway.

In this matter, in the Brain, Behavior, and Immunity study, Bassi and colleagues found that afferent VNS reduced joint arthritis independently on the integrity of peripheral structures, as the spleen, adrenal glands, the celiac vagus, or lymphocyte activity, or cardiovascular alterations.

The vagal effect decreased synovial ICAM-1 expression and was blocked by prior sympathectomy. In fact, VNS increased c-Fos expression (a neuronal activity marker) in two specific brain sympathomodulatory brain nuclei, the hypothalamic paraventricular nucleus (PVN) and the locus coeruleus (LC). The authors then suggested that those nuclei may have immunomodulatory properties.

Of note, non-aversive electrical stimulation of the PVN or LC improved arthritis score and decreased neutrophilic infiltration into the synovial tissue, showing, for the first time, the existence of specific inflammatory processing brain areas controlling arthritis inflammation.

The authors also investigated whether these structures were involved in the VNS anti-inflammatory response. By injecting cobalt chloride (a synapse activity blocker) into the right PVN or right LC, the authors showed that the inhibition of the LC, but not PVN, blocked the vagal effect.

Importantly, the integrity of the LC, but not that of PVN, was critical for vagal regulation of arthritic joint inflammation. Of note, only the ipsilateral side joint (right knee) to the LC lesion improved arthritis score and reduced neutrophilic infiltration, suggesting the existence of a unilateral immunomodulatory pathway connecting LC and the knee joint.

The present study provides, for the first time, the dissection of a new central neuroimmune anti-inflammatory pathway dependent on specific sympathomodulatory brain areas, local sympathetic activation, joint β-adrenergic mechanisms and inhibition of synovial ICAM-1 expression.

The study is opening up new avenues to the discovery of other potential brain immunomodulatory structures (immunological homunculus) and to the understanding of placebo effect, acupuncture, and how mental status can alter the immune profile.

SourceBrain Behav Imm, 2017; 64:330-343. doi: 10.1016/j.bbi.2017.04.003.
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