Systemic inflammation regulates microglial responses to tissue damagein vivo

Abstract

Microglia, the resident immune cells of the central nervous system, exist in either a “resting” state associated with physiological tissue surveillance or an “activated” state in neuroinflammation. We recently showed that ATP is the primary chemoattractor to tissue damage in vivo and elicits opposite effects on the motility of activated microglia in vitro through activation of adenosine A2A receptors. However, whether systemic inflammation affects microglial responses to tissue damage in vivo remains largely unknown. Using in vivo two-photon imaging of mice, we show that injection of lipopolysaccharide (LPS) at levels that can produce both clear neuroinflammation and some features of sepsis significantly reduced the rate of microglial response to laser-induced ablation injury in vivo. Under pro-inflammatory conditions, microglial processes initially retracted from the ablation site, but subsequently moved toward and engulfed the damaged area. Analyzing the process dynamics in 3D cultures of primary microglia indicated that only A2A, but not A1 or A3 receptors, mediate process retraction in LPS-activated microglia. The A2A receptor antagonists caffeine and preladenant reduced adenosine-mediated process retraction in activated microglia in vitro. Finally, administration of preladenant before induction of laser ablation in vivo accelerated the microglial response to injury following systemic inflammation. The regulation of rapid microglial responses to sites of injury by A2A receptors could have implications for their ability to respond to the neuronal death occurring under conditions of neuroinflammation in neurodegenerative disorders.

A close look at brain dynamics: Cells and vessels seen by in vivo two-photon microscopy

“…In contrast, the expression of P2Y 12 R decreases (Haynes et al, 2006;Orr et al, 2009). This pathway is also responsible for the microglia displacement induced by LPS stimulation (Gyoneva et al, 2014;Ohsawa and Kohsaka, 2011).…”

Altered motility of plaque-associated microglia in a model of Alzheimer’s disease

“…However, when microglia become activated by toll-like receptor activation or Aβ peptides, they downregulate their P2Y12 receptors and upregulate adenosine A2A receptors at the mRNA level in vitro (Orr et al, 2009). A2A receptor activation by the ATP breakdown product adenosine leads to process retraction by activated microglia in vitro (Orr et al, 2009), and impairs microglial responses to tissue damage in models of systemic inflammation and Parkinson’s disease (PD) (Gyoneva et al, 2014a; Gyoneva et al, 2014b). …”

“…Consumption of caffeine, a nonselective adenosine receptor antagonist, has been linked to a lower risk for developing AD (Eskelinen and Kivipelto, 2010; Santos et al, 2010), as well as reduced neuronal loss, lowered Aβ levels and improved cognition in animal models of AD (Arendash et al, 2009; Canas et al, 2009; Cao et al, 2009). Caffeine also blocks the actions of adenosine on microglial motility (Gyoneva et al, 2014a), raising the possibility that this contributes to its role in AD. Microglia in a mouse model of AD show a reduced response to tissue damage by laser ablation (Krabbe et al, 2013), although the involvement of A2A receptors in modulating microglial motility has not been evaluated in models of AD.…”

Receptors, Ion Channels, and Signaling Mechanisms Underlying Microglial Dynamics

“…Strikingly, this shift of receptor expression reversed the chemotactic response to ATP in activated microglia, triggering process retraction and even migratory repulsion (in vitro) (29). Nevertheless, LPS-activated microglia in vivo can still respond to laser-induced tissue damage by sending out processes, despite initially responding by transiently retracting their processes (45).…”

“…Finally, our review has focused on resting microglia. Further work is needed to reveal which other mechanisms exist to evoke a targeted response of microglial processes under pathological conditions when activated microglia have substantially down-regulated their P2Y 12 receptor expression (29,45). It will also be important to understand whether the properties of microglia generated from macrophages that invade the brain following injury differ from those of yolk sac-derived endogenous microglia.…”