Astrocytes as Active Players of the Innate Immune System: Another Layer of Astroglial Heterogeneity?

Abstract

Reactive gliosis involving activation and proliferation ofastrocytes and microglia is a widespread but largely complexand graded glial response to brain injury. Astroglial populationhas a previously underestimated high heterogeneitywith cells differing in their morphology, gene expressionprofile, and response to injury. Over the last years, wehave been studying whether astrocytes may behave as facultativeinnate immunity cells after central nervous systeminjury. Classical innate immunity activation in the absenceof infection relies on the damage-associated molecular patterns(DAMP) release by dying cells. DAMPs behave asligands of the pattern recognition receptors, such as Tolllikereceptor, RAGE, and others. Using a combination ofmathematical modeling, in vitro and in vivo experimentation,we have been able to show that astrocytes essentially behaveas facultative cells of the innate immunity response that classically follows brain damage.While classical innate immunitypathways such as those involving RAGE, Toll-like receptor4/nuclear factor-jB, and TREM-2 are activated byreleased DAMPs, astrocytes are also key players in determiningthe interaction with local and peripheral professionalimmune cells. Moreover, detailed histological studies andex vivo culture experiments have shown that only a subsetof astrocytes seems to have the immune and neuroinflammatoryrole in experimental focal brain lesions and they canbe specifically targeted by dendrimeric nanoparticles. Thisadditional layer of neurobiological complexity can also beexplored for therapeutic purposes oriented toward controllingneuroinflammation in the injured brain.