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

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.

Keywords: aging; cell–cell interactions; extracellular matrix; inflammation; neurodegenerative diseases.

Figure 1

(A–C) Ca²⁺ dependent cytoskeletal remodeling is involved in microglial branching. Microglia in the CA1 hippocampus of adult control rats (A), adult rats treated with lipopolysaccharide (LPS) infusion (1.6 mg/mL LPS, 4 weeks) to induce neuroinflammation (B), and aged rats (C) were stained to reveal Iba1 (16-color LUT), a marker of cytoskeletal remodeling. In LPS-treated rats (B) microglia show increased branching and expression of Iba1 in comparison with control rats (A). In aged rats (C), microglia display elongated soma and limited branching [33]. (D–F) Microglial branching and density of the meshwork formed by astrocyte processes are correlated. Microglia and astrocytes in the CA1 hippocampus of adult control (D), adult LPS-treated (E), and aged (F) rats were immunostained to reveal Iba1 (yellow LUT) and GFAP (magenta LUT). Insets d–g) Details of the areas selected in (D) (inset d), (E) (inset e) and (F) (insets f and g), showing cell–cell contacts (cyan LUT). Increased branching and Iba1 expression of microglia in LPS—treated with respect to control—rats appear directly correlated with a proportional increase of astrocyte meshwork density (D,E) and cell–cell contacts (insets d,e). The same correlation was found in aged rats (F): branched microglia (inset f1) were found within intact astrocyte meshwork establishing numerous cell—cell contacts (inset f2), whereas amoeboid unbranched microglia (inset g1) were found in areas showing meshwork disruption (inset g2) [33]. G) Contacts between astrocytes and autofluorescent deposits of denatured peptides on neurons promote process fragmentation. Sections of the CA1 hippocampus of LPS-treated rats were immunostained to reveal GFAP (blue LUT); autofluorescence of denatured peptides was also collected (yellow LUT). Insets 1 and 2, details of the areas selected in (G). Astrocyte processes diffusely contact denatured peptides produced by the neurons of the stratum pyramidale (dashed lines). Arrows in inset 1 indicate a deposit (1a) of denatured peptides on a fracturing astrocyte process. Arrowheads in inset 2 indicate two peptide deposits associated with a GFAP+ fragment [55]. Scale bars: A–C, G = 25 µm; D–F = 40 µm; Insets d, e = 10 µm; Insets f, g = 5 µm; Insets 1, 2 = 3 µm.