Spinal GABA-B receptor modulates neutrophil recruitment to the knee joint in zymosan-induced arthritis

Abstract

Recent studies have demonstrated that the central nervous system controls inflammatory responses by activating complex efferent neuroimmune pathways. The present study was designed to evaluate the role that central gamma-aminobutyric acid type B (GABA-B) receptor plays in neutrophil migration in a murine model of zymosan-induced arthritis by using different pharmacological tools. We observed that intrathecal administration of baclofen, a selective GABA-B agonist, exacerbated the inflammatory response in the knee after zymosan administration characterized by an increase in the neutrophil recruitment and knee joint edema, whereas saclofen, a GABA-B antagonist, exerted the opposite effect. Intrathecal pretreatment of the animals with SB203580 (an inhibitor of p38 mitogen-activated protein kinase) blocked the pro-inflammatory effect of baclofen. On the other hand, systemic administration of guanethidine, a sympatholytic drug that inhibits catecholamine release, and nadolol, a beta-adrenergic receptor antagonist, reversed the effect of saclofen. Moreover, saclofen suppressed the release of the pro-inflammatory cytokines into the knee joint (ELISA) and pain-related behaviors (open field test). Since the anti-inflammatory effect of saclofen depends on the sympathetic nervous system integrity, we observed that isoproterenol, a beta-adrenergic receptor agonist, mimics the central GABA-B blockade decreasing knee joint neutrophil recruitment. Together, these results demonstrate that the pharmacological manipulation of spinal GABAergic transmission aids control of neutrophil migration to the inflamed joint by modulating the activation of the knee joint-innervating sympathetic terminal fibers through a mechanism dependent on peripheral beta-adrenergic receptors and central components, such as p38 MAPK.

Inhibition of spinal p38 MAPK prevents articular neutrophil infiltration in experimental arthritis via sympathetic activation

“…The present data complement our previous studies demonstrating the existence of an elaborate neuroimmune route constituted by peripheral and central components [6][7][8] adding the spinal p38 MAPK as proinflammatory component involved in the progression of joint inflammation. Finally, our study also suggests the design of innovative strategies that could show clinical advantages as compared to the current pharmacological therapy.…”

“…The potential use of this neuroimmune pathway was investigated only in zymosan‐induced arthritis, in which it has been observed only local inflammation and innate immune response. However, this classical model has allowed the investigation of a specific neural network involved in the modulation of joint inflammation and, together with previous experimental data, reinforces the potential role of central p38 MAPK inhibition in joint inflammatory diseases . Further studies in other experimental models, as collagen‐induced arthritis, are needed to validate this therapeutic approach in rheumatoid arthritis treatment.…”

“…Next we analyzed the neuronal mechanisms mediating the effects of inhibiting spinal p38 MAPK in arthritis. We recently reported that electrical stimulation of the peripheral sympathetic networks prevents neutrophil infiltration into the arthritic knee joint . Thus, we analyzed whether chemical sympathectomy abolishes the improvement in arthritic induced by pharmacological inhibition of p38 MAPK.…”

“…On the other hand, pharmacological blockade of spinal p38 MAPK suppressed synovial inflammation and joint destruction in chronic arthritic rats [11]. Given that our previous data demonstrated that spinal GABAergic circuits amplify neutrophil migration in experimental arthritis and that these circuits signal via p38 MAPK [6], we analyzed whether inhibition of spinal p38 MAPK affects knee joint inflammation. Our present study shows that inhibition of spinal p38 MAPK prevents arthritic knee joint inflammation via sympathetic networks and beta-adrenoceptors activation inhibiting neutrophil infiltration and cytokine production.…”

The immunological function of GABAergic system

“…GABA B receptor is expressed in neutrophils, and acts as chemoattractant receptor, which has significant roles in inflammatory responses (56). In zymosan-induced arthritis, GABA B receptor participates in neutrophil migration to the knee joint, which may attribute to spinal activation of p38 MAPK (57). Likewise, baclofen (GABA B receptors agonist) prevents loss of the expression of GABA B receptor after acute lung injury, and significantly inhibits the release of TNF-α and IL-1 receptor accessory protein (IL-1R AcP), while concurrently promotes the apoptosis of neutrophils in the bronchoalveolar lavage (58).…”