Thomas Meinel1, Georg Pongratz, Luise Rauch, Rainer H Straub. 1. Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine, University Hospital Regensburg, 93042 Regensburg, Germany.
Abstract
OBJECTIVE: Functional cross-talk exists between sympathetic nerve fibers and cytokine-producing splenic cells in early collagen type II-induced arthritis (CIA) (day 32). These earlier experiments demonstrated exclusively neuronal sympathetic regulation of IFN-γ, CXCL1, IL-6, and TGF-β. However, in late arthritis, the sympathetic influence might change due to loss of sympathetic nerve fibers and appearance of neurotransmitter-producing cells. We aimed to investigate neurotransmitter-dependent regulation of IFN-γ, CXCL1, IL-6, and TGF-β in murine spleen in late CIA. METHODS: Spleens were removed when animals reached day 58 (46-68) after immunization to generate 0.35 mm-thick spleen slices, which were transferred to superfusion microchambers to electrically induce release of neurotransmitters. Using respective neurotransmitter antagonists, effects of released neurotransmitters on cytokine secretion were investigated. RESULTS: There was electrically induced inhibition of IFN-γ, CXCL1, and IL-6, and stimulation of TGF-β, which was much less pronounced than in early CIA. There existed β adrenergic inhibition of IFN-γ, IL-6, and TGF-β (and stimulation of CXCL1) independent of electrical stimulation (interpreted as non-neuronal). However, there was a neuronal α1/2 adrenergic stimulation of IFN-γ, CXCL1, and IL-6 and, we observed neuronal A1-adenosinergic stimulation of TGF-β. CONCLUSIONS: In the late phase of CIA, non-neuronal modulation of cytokine secretion increases while neuronal regulation strikingly decreases. Particularly, β-adrenergic effects are non-neuronal while α1/2-adrenergic effects are clearly neuronal. We suggest that alterations in sympathetic innervation of the spleen fundamentally change the functional neuroimmune interplay in the spleen of arthritic mice.
OBJECTIVE: Functional cross-talk exists between sympathetic nerve fibers and cytokine-producing splenic cells in early collagen type II-induced arthritis (CIA) (day 32). These earlier experiments demonstrated exclusively neuronal sympathetic regulation of IFN-γ, CXCL1, IL-6, and TGF-β. However, in late arthritis, the sympathetic influence might change due to loss of sympathetic nerve fibers and appearance of neurotransmitter-producing cells. We aimed to investigate neurotransmitter-dependent regulation of IFN-γ, CXCL1, IL-6, and TGF-β in murine spleen in late CIA. METHODS: Spleens were removed when animals reached day 58 (46-68) after immunization to generate 0.35 mm-thick spleen slices, which were transferred to superfusion microchambers to electrically induce release of neurotransmitters. Using respective neurotransmitter antagonists, effects of released neurotransmitters on cytokine secretion were investigated. RESULTS: There was electrically induced inhibition of IFN-γ, CXCL1, and IL-6, and stimulation of TGF-β, which was much less pronounced than in early CIA. There existed β adrenergic inhibition of IFN-γ, IL-6, and TGF-β (and stimulation of CXCL1) independent of electrical stimulation (interpreted as non-neuronal). However, there was a neuronal α1/2 adrenergic stimulation of IFN-γ, CXCL1, and IL-6 and, we observed neuronal A1-adenosinergic stimulation of TGF-β. CONCLUSIONS: In the late phase of CIA, non-neuronal modulation of cytokine secretion increases while neuronal regulation strikingly decreases. Particularly, β-adrenergic effects are non-neuronal while α1/2-adrenergic effects are clearly neuronal. We suggest that alterations in sympathetic innervation of the spleen fundamentally change the functional neuroimmune interplay in the spleen of arthritic mice.