Astrocyte Reactivity: Subtypes, States, and Functions in CNS Innate Immunity

Highlights

• Astrocyte reactivity in response to different central nervous system (CNS) disorders is diverse and context-dependent, and can be functionally powerful.

• Reactive astrocytes exhibit at least two broad overarching subtypes: (i) proliferative border-forming reactive astrocytes that surround areas of overt tissue damage, and (ii) nonproliferative reactive astrocytes that retain their basic structure and cellular interactions in essentially intact but reactive neural tissue.

• Normal astrocyte reactivity is an evolutionarily ancient response that can protect neural tissue, maintain tissue homeostasis, and preserve neurological functions after diverse CNS insults.

• Dysfunction of reactive astrocytes can contribute to CNS disorders either through loss of normal functions or through gain of abnormal functions.

• Reactive astrocytes express damage-associated molecular patterns (DAMP) and pathogen-associated molecular pattern (PAMP) receptors, and are emerging as integral and essential components of multicellular CNS innate immunity.

Astrocytes are neural parenchymal cells that ubiquitously tile the central nervous system (CNS). In addition to playing essential roles in healthy tissue, astrocytes exhibit an evolutionarily ancient response to all CNS insults, referred to as astrocyte reactivity. Long regarded as passive and homogeneous, astrocyte reactivity is being revealed as a heterogeneous and functionally powerful component of mammalian CNS innate immunity. Nevertheless, concepts about what astrocyte reactivity comprises and what it does are incomplete and sometimes controversial. This review discusses the goal of differentiating reactive astrocyte subtypes and states based on composite pictures of molecular expression, cell morphology, cellular interactions, proliferative state, normal functions, and disease-induced dysfunctions. A working model and conceptual framework is presented for characterizing the diversity of astrocyte reactivity.