Astrocyte Responses to Complement Peptide C3a are Highly Context-Dependent

Abstract

Astrocytes perform a range of homeostatic and regulatory tasks that are critical for normal functioning of the central nervous system. In response to an injury or disease, astrocytes undergo a pronounced transformation into a reactive state that involves changes in the expression of many genes and dramatically changes astrocyte morphology and functions. This astrocyte reactivity is highly dependent on the initiating insult and pathological context. C3a is a peptide generated by the proteolytic cleavage of the third complement component. C3a has been shown to exert neuroprotective effects, stimulate neural plasticity and promote astrocyte survival but can also contribute to synapse loss, Alzheimer’s disease type neurodegeneration and blood–brain barrier dysfunction. To test the hypothesis that C3a elicits differential effects on astrocytes depending on their reactivity state, we measured the expression of Gfap, Nes, C3ar1, C3, Ngf, Tnf and Il1b in primary mouse cortical astrocytes after chemical ischemia, after exposure to lipopolysaccharide (LPS) as well as in control naïve astrocytes. We found that C3a down-regulated the expression of Gfap, C3 and Nes in astrocytes after ischemia. Further, C3a increased the expression of Tnf and Il1b in naive astrocytes and the expression of Nes in astrocytes exposed to LPS but did not affect the expression of C3ar1 or Ngf. Jointly, these results provide the first evidence that the complement peptide C3a modulates the responses of astrocytes in a highly context-dependent manner.

Astrocytes in human central nervous system diseases: a frontier for new therapies

“…As noted above, astrocyte reactivity is associated with diverse changes in molecular expression that can vary from mild to pronounced and that are highly context dependent. Increases in the expression of various molecules that have been noted in reactive astrocytes across multiple contexts include GFAP, vimentin, nestin (probably labelling proliferating astrocytes), synemin plectin, α-crystallin B chain, monoaminoxodase-B (MAO-B), heat shock factor binding protein 1, complement C3, lipocalin 2, C-X-C motif chemokine ligand 10, SerpinA3N, LCN2 and others, 20,[95][96][97][98][99][100][101][102][103] but it important to note that no single molecular marker (including GFAP) is an absolute, required and sufficient, indicator of astrocyte reactivity, and no molecular markers have yet been identified that reliably distinguish amongst different reactive astrocyte phenotypes. In the future, rather than look for additional global markers of astrogliosis, it will likely be more useful to look for molecules upregulated by astrocytes in specific contexts and that are associated with specific functions or effects of astrogliosis.…”

Mechanisms of immune response and cell death in ischemic stroke and their regulation by natural compounds

“…After IS, damaged cells produce and release cytokines and DAMPs to stimulate receptors of astrocytes and change their phenotype. A few minutes after IS, due to reactive astrocyte proliferation, astrocytes respond to various inflammatory factors (including TGF-α, ciliary neurotrophic factor, IL-1, IL-6, and kallikrein-related peptidase 6) released by ischemic/hypoxic cells, and are subsequently activated and reproduced ( 69 , 70 ). Reactive astrogliosis occurs in the peri-infarct region, and a glial scar is formed to maintain CNS homeostasis and wall off the lesion ( 71 ).…”