Modulation by Astrocytes of Microglial Cell-Mediated Neuroinflammation: Effect on the Activation of Microglial Signaling Pathways

Abstract

The strong inflammatory response observed in neurodegenerative diseases can depend on the impairment of the endogenous control of microglial activation, triggering the release of potentially detrimental factors such as cytokines, nitric oxide (NO) and superoxide anion (O₂^–·). Our aim was to study the activation of microglial cells and the transduction pathways involved in their modulation by IL-1β and TNF-α. Microglial and mixed glial cell cultures from neonatal rats were exposed to IFN-γ and/or IL-1β and TNF-α. We analyzed NO secretion and the activation of ERK and STAT1. We found that astrocytes modulated microglial cell activation, decreasing production of NO. IFN-γ induced an 18- to 25-fold increase in NO, associated to a 3- to 5-fold increase in ERK phosphorylation in microglial cultures. IL-1β, but not TNF-α, inhibited IFN-γ-induced production of NO in microglia by 87%. It also reduced IFN-γ-induced phosphoERK (pERK) by 40%, without affecting phosphoSTAT1 (pSTAT1). In contrast, in microglial cultures exposed to media conditioned by astrocytes, IL-1β did not inhibit pERK, whereas it reduced activation of STAT1. Inducible NO synthase expression induced by IFN-γ in microglial cultures was reduced when the activation of ERK was prevented. We propose that IL-1β modulates IFN-γ-induced production of oxidative molecules through cross talk between STAT1 and MAPK pathways, regulating the amplitude and duration of microglial activation. Modulation of ERK was observed at 30 min, whereas inhibition of pSTAT was observed later (at 4 h), indicating that it was an early and transient phenomenon.

Hypoxia-Induced Gene Expression of Aquaporin-4, Cyclooxygenase-2 and Hypoxia-Inducible Factor 1α in Rat Cortical Astroglia Is Inhibited by 17β-Estradiol and Progesterone

“…This immune cell type produces a number of proinflammatory cytokines and chemokines besides other inflammatory and toxic factors (inducible nitric oxide synthase, PGE 2 ) and accounts for cell degeneration. On the other hand, there is extensive cross talk between all types of glial cells during pathophysiological processes in the CNS where a reciprocal regulatory influence in ischemia and neurodegenerative diseases can be observed encompassing astroglia and microglia [35,36] . Sex steroids therefore might affect microglia and thereby modulate astroglial function.…”

Astrocytes inhibit nitric oxide-dependent Ca2+dynamics in activated microglia: Involvement of ATP released via pannexin 1 channels

“…To assess the release of NO, nitrites, a stable derivative of NO, were measured as previously reported (Tichauer et al, 2007). Under control conditions, microglia did not exhibit a significant variation in nitrite levels ( Fig.…”

Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system

“…Astrocytes have been reported to decrease the production of NO, reactive oxygen species (ROS) and TNF-α from microglia (von Bernhardi and Eugenín, 2004;Smits et al, 2001;Tichauer et al, 2007). Besides, the ability of microglial phagocytizing and removing senile plaque (SP) was markedly suppressed when cocultured with astrocytes.…”