Role of RGC-32 in multiple sclerosis and neuroinflammation - few answers and many questions

Abstract

Recent advances in understanding the pathogenesis of multiple sclerosis (MS) have brought into the spotlight the major role played by reactive astrocytes in this condition. Response Gene to Complement (RGC)-32 is a gene induced by complement activation, growth factors, and cytokines, notably transforming growth factor β, that is involved in the modulation of processes such as angiogenesis, fibrosis, cell migration, and cell differentiation. Studies have uncovered the crucial role that RGC-32 plays in promoting the differentiation of Th17 cells, a subtype of CD4⁺ T lymphocytes with an important role in MS and its murine model, experimental autoimmune encephalomyelitis. The latest data have also shown that RGC-32 is involved in regulating major transcriptomic changes in astrocytes and in favoring the synthesis and secretion of extracellular matrix components, growth factors, axonal growth molecules, and pro-astrogliogenic molecules. These results suggest that RGC-32 plays a major role in driving reactive astrocytosis and the generation of astrocytes from radial glia precursors. In this review, we summarize recent advances in understanding how RGC-32 regulates the behavior of Th17 cells and astrocytes in neuroinflammation, providing insight into its role as a potential new biomarker and therapeutic target.

Keywords: EAE (experimental autoimmune encephalomyelitis); RGC-32; Th17; astrocyte; multiple sclerosis; neuroinflammation; radial glia.

Figure 1

Schematic representation of the molecular pathways regulated by RGC-32 during Th17 cell differentiation. RGC-32 is upregulated in naïve CD4⁺ T cells cultured under Th17 differentiating conditions. Our studies showed that lack of RGC-32 impairs the expression of critical transcription factors involved in Th17 cell differentiation, such as the master regulator RORγt, IRF4 and BATF. The phosphorylation of SMAD2 downstream of TGF-β receptor activation might be one of the major pathways positively regulated by RGC-32 during Th17 cells generation. Th17 cells play a major role in neuroinflammatory changes at the peak of EAE mediated primarily by IL-17 and GM-CSF, that exert important chemotactic properties. (Created with BioRender.com).

Figure 2

Schema depicting the main molecular and cellular processes influenced by RGC-32 in astrocytes during EAE. Data show that RGC-32 plays a major role in driving changes specific to reactive astrocytosis, such as cellular hypertrophy and glial scar formation, by favoring GFAP upregulation and synthesis of ECM components. The secretion of growth factors and AGM with BBB leakage and tissue damage potential point to a mainly pathogenic role of RGC-32, at least during acute EAE. On the other hand, RGC-32 seems to have astrogliogenic potential, since a lack of RGC-32 results in a higher number of radial glia and astrocyte precursors in adult mice. Since adult radial glial cells are a major source of reactive astrocytes in the spinal cords during EAE, it is also highly possible that RGC-32 favors this direct transition. (Created with BioRender.com).