Increased astrocyte expression of IL-6 or CCL2 in transgenic mice alters levels of hippocampal and cerebellar proteins.

Donna L Gruol,Khanh Vo,Jennifer G Bray

doi:10.3389/fncel.2014.00234

Abstract

Emerging research has identified that neuroimmune factors are produced by cells of the central nervous system (CNS) and play critical roles as regulators of CNS function, directors of neurodevelopment and responders to pathological processes. A wide range of neuroimmune factors are produced by CNS cells, primarily the glial cells, but the role of specific neuroimmune factors and their glial cell sources in CNS biology and pathology have yet to be fully elucidated. We have used transgenic mice that express elevated levels of a specific neuroimmune factor, the cytokine IL-6 or the chemokine CCL2, through genetic modification of astrocyte expression to identify targets of astrocyte produced IL-6 or CCL2 at the protein level. We found that in non-transgenic mice constitutive expression of IL-6 and CCL2 occurs in the two CNS regions studied, the hippocampus and cerebellum, as measured by ELISA. In the CCL2 transgenic mice elevated levels of CCL2 were evident in the hippocampus and cerebellum, whereas in the IL-6 transgenic mice, elevated levels of IL-6 were only evident in the cerebellum. Western blot analysis of the cellular and synaptic proteins in the hippocampus and cerebellum of the transgenic mice showed that the elevated levels of CCL2 or IL-6 resulted in alterations in the levels of specific proteins and that these actions differed for the two neuroimmune factors and for the two brain regions. These results are consistent with cell specific profiles of action for IL-6 and CCL2, actions that may be an important aspect of their respective roles in CNS physiology and pathophysiology.

Highlights

IntroductionImmune factors that play a critical role in the peripheral immune system, such as cytokines and chemokines, are known to be produced within the central nervous system (CNS) by cells of the CNS and to play important roles in normal CNS functions as well as pathological states (Gruol and Nelson, 1997; Glabinski and Ransohoff, 1999; Bajetto et al, 2001; Banisadr et al, 2005; Deverman and Patterson, 2009; Spooren et al, 2011; Erta et al, 2012; Arisi, 2014)
Immune factors produced by central nervous system (CNS) cells are referred to as neuroimmune factors to distinguish their origin from immune factors that are produced by cells of the peripheral immune system trafficketing through the CNS
IL-6 AND CCL2 EXPRESSION Levels of IL-6 and CCL2 in hippocampus and cerebellum of transgenic and non-transgenic mice at different ages were determined by ELISA

Summary

Introduction

Immune factors that play a critical role in the peripheral immune system, such as cytokines and chemokines, are known to be produced within the CNS by cells of the CNS and to play important roles in normal CNS functions as well as pathological states (Gruol and Nelson, 1997; Glabinski and Ransohoff, 1999; Bajetto et al, 2001; Banisadr et al, 2005; Deverman and Patterson, 2009; Spooren et al, 2011; Erta et al, 2012; Arisi, 2014). The primary source of neuroimmune factors in the CNS is glial cells (astrocytes and microglia) (Kettenmann et al, 2011; Smith et al, 2012; Jensen et al, 2013; Choi et al, 2014). If the production of neuroimmune factors becomes dysregulated, the elevated levels may promote pathological processes rather than ameliorate the negative effects of adverse conditions

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Conclusion