Neuronal α1/2-adrenergic stimulation of IFN-γ, IL-6, and CXCL-1 in murine spleen in late experimental arthritis

Abstract

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. 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. 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. 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.