Neuroinflammation: Integrated Nervous Tissue Response through Intercellular Interactions at the "Whole System" Scale.

Daniele Nosi,Daniele Lana,Sandra Zecchi-Orlandini,Giovanni Delfino,Maria Grazia Giovannini

doi:10.3390/cells10051195

Abstract

Different cell populations in the nervous tissue establish numerous, heterotypic interactions and perform specific, frequently intersecting activities devoted to the maintenance of homeostasis. Microglia and astrocytes, respectively the immune and the “housekeeper” cells of nervous tissue, play a key role in neurodegenerative diseases. Alterations of tissue homeostasis trigger neuroinflammation, a collective dynamic response of glial cells. Reactive astrocytes and microglia express various functional phenotypes, ranging from anti-inflammatory to pro-inflammatory. Chronic neuroinflammation is characterized by a gradual shift of astroglial and microglial phenotypes from anti-inflammatory to pro-inflammatory, switching their activities from cytoprotective to cytotoxic. In this scenario, the different cell populations reciprocally modulate their phenotypes through intense, reverberating signaling. Current evidence suggests that heterotypic interactions are links in an intricate network of mutual influences and interdependencies connecting all cell types in the nervous system. In this view, activation, modulation, as well as outcomes of neuroinflammation, should be ascribed to the nervous tissue as a whole. While the need remains of identifying further links in this network, a step back to rethink our view of neuroinflammation in the light of the “whole system” scale, could help us to understand some of its most controversial and puzzling features.

Highlights

In the central nervous system (CNS), a basic classification of the different cell populations can be formulated, according to their specific activities under normal and pathological conditions
The identification and characterization of microglial phenotypes in neuroinflammation led to the development of several therapeutic strategies against neurodegenerative diseases [24,25], which aim at reverting the neurodegenerative polarization of microglia
The pattern of diverse interactions occurring between astrocyte-microglia in neuroinflammation has been the object of intense scientific investigation in recent years, due to its relevance in diffused and dramatic pathologies

Summary

Introduction

In the central nervous system (CNS), a basic classification of the different cell populations can be formulated, according to their specific activities under normal and pathological conditions. If we assume that the ubiquitous meshwork of astrocyte projections may be the first glial structure making physical contact with pro-inflammatory molecules in the nervous tissue, the effects of such cytotoxic interactions on astrocytes and on their activities should be carefully pondered These considerations hint that the identification of a reliable sequence of mutual inductions and interdependencies linking astrocytes and microglia could be deduced by integrating their patterns of inflammatory activation and phenotype polarization. Increasing knowledge of such sequential relationships is leading to relevant advances in the field of neurodegenerative diseases. We believe that this approach could be fruitfully adopted to conceive new diriment questions and highlight unexpected features of the unsolved enigma of neuroinflammation

Neuroglia

Microglia in Neuroinflammation

Astrocytes in Neuroinflammation

In Neuroinflammation

Conclusions