Modulation of experimental arthritis by vagal sensory and central brain stimulation

Abstract

Articular inflammation is a major clinical burden in multiple inflammatory diseases, especially in rheumatoid arthritis. Biological anti-rheumatic drug therapies are expensive and increase the risk of systemic immunosuppression, infections, and malignancies. Here, we report that vagus nerve stimulation controls arthritic joint inflammation by inducing local regulation of innate immune response. Most of the previous studies of neuromodulation focused on vagal regulation of inflammation via the efferent peripheral pathway toward the viscera. Here, we report that vagal stimulation modulates arthritic joint inflammation through a novel "afferent" pathway mediated by the locus coeruleus (LC) of the central nervous system. Afferent vagal stimulation activates two sympatho-excitatory brain areas: the paraventricular hypothalamic nucleus (PVN) and the LC. The integrity of the LC, but not that of the PVN, is critical for vagal control of arthritic joint inflammation. Afferent vagal stimulation suppresses articular inflammation in the ipsilateral, but not in the contralateral knee to the hemispheric LC lesion. Central stimulation is followed by subsequent activation of joint sympathetic nerve terminals inducing articular norepinephrine release. Selective adrenergic beta-blockers prevent the effects of articular norepinephrine and thereby abrogate vagal control of arthritic joint inflammation. These results reveals a novel neuro-immune brain map with afferent vagal signals controlling side-specific articular inflammation through specific inflammatory-processing brain centers and joint sympathetic innervations.

Baroreflex stimulation attenuates central but not peripheral inflammation in conscious endotoxemic rats

“…These findings suggest that the central baroreflex anti-inflammatory mechanism is independent of cardiovascular alterations. In line with our results, vagal stimulation at high intensity produces hemodynamic alterations but not anti-inflammatory effects, while low intensity vagal stimulation induces immunomodulatory properties without promoting hemodynamic alterations (Bassi et al, 2017). Thus, our results indicate that during parasympathetic activation, it is not essential for changes in the hemodynamic parameters to occur in order for an anti-inflammatory effect to occur.…”

Brain Stimulation Differentially Modulates Nociception and Inflammation in Aversive and Non-aversive Behavioral Conditions

“…Recent studies on alternative therapies to control inflammation showed a bidirectional interaction between nervous and the immune systems (Olofsson et al, 2012; Torres-Rosas et al, 2014; Bassi et al, 2015, 2017; Ulloa et al, 2017). Electrical nerve stimulation can represent a promising strategy to control inflammation without the effects of current pharmacological treatments (Olofsson et al, 2012; Bassi et al, 2015, 2017; Ulloa and Deitch, 2009).…”

“…Electrical nerve stimulation can represent a promising strategy to control inflammation without the effects of current pharmacological treatments (Olofsson et al, 2012; Bassi et al, 2015, 2017; Ulloa and Deitch, 2009). Clinical and experimental studies indicate that peripheral or central neural stimulation attenuates joint inflammation (Miao et al, 2003; Kox et al, 2014; Bassi et al, 2015, 2017; Koopman et al, 2016) and pain sensitivity (Mayer and Liebeskind, 1974; Basbaum and Fields, 1984; Ren et al, 1988; de Luca et al, 2003; Busch et al, 2013) in diverse models of experimental arthritis. We recently reported that electrical stimulation of brain structures, including the locus coeruleus (LC) or the paraventricular nucleus (PVN), decreases joint inflammation without affecting rat behavior (Bassi et al, 2017).…”

“…Clinical and experimental studies indicate that peripheral or central neural stimulation attenuates joint inflammation (Miao et al, 2003; Kox et al, 2014; Bassi et al, 2015, 2017; Koopman et al, 2016) and pain sensitivity (Mayer and Liebeskind, 1974; Basbaum and Fields, 1984; Ren et al, 1988; de Luca et al, 2003; Busch et al, 2013) in diverse models of experimental arthritis. We recently reported that electrical stimulation of brain structures, including the locus coeruleus (LC) or the paraventricular nucleus (PVN), decreases joint inflammation without affecting rat behavior (Bassi et al, 2017). Other studies reported that stimulation of these brain areas can decrease nociception and pain sensitivity (Panksepp, 1971; Fuchs et al, 1985; West et al, 1993; Hickey et al, 2014) in aversive defensive responses such as that displayed by prey during a predator attack (Gallup, 1977; Yardley and Hilton, 1986; Coimbra et al, 2017).…”

A Promising New Approach for the Treatment of Inflammatory Pain: Transfer of Stem Cell-Derived Tyrosine Hydroxylase-Positive Cells

“…In this context, it was found that chemical sympathectomy before disease manifestation significantly attenuated arthritis in models such as collagen-induced polyarthritis (CIA) or monoarticular antigen-induced arthritis (AIA). However, in the advanced chronic stage of CIA, the sympathetic nervous system may rather dampen inflammation [4, 5]. At the same time, however, sympathetic nerve fibers may be removed from the tissue, thus raising the question whether the potentially anti-inflammatory sympathetic influence still exists [6].…”