Cytokine and chemokine production by astrocytes is influenced by Cystatin C

Astrocytes play essential roles during homeostasis as structural and functional components of tripartite synapse signaling, blood brain barrier integrity, and neurotransmitter buffering. However, these glia can become reactive in diseases such as multiple sclerosis (MS), where they can exacerbate pro-inflammatory environments by recruiting and promoting immune cell activity through secretion of cytokines and chemokines and possibly antigen presentation. What is incompletely known are the molecular regulators of astrocyte activation. Variable levels of Cst3 mRNA and Cystatin C (CysC) protein have been recorded in a variety of MS tissues, and CysC plays a detrimental role in the experimental autoimmune encephalomyelitis (EAE) model of MS. Further, CysC promotes glial fibrillary acidic protein (Gfap) expression, and contributes to the number of GFAP-positive cells during development. As such, we investigated if CysC is expressed by astrocytes in MS and EAE central nervous system (CNS) cord tissue, and what the functional consequence may be of CysC expression in these glia. We found that CysC is robustly expressed by astrocytes in MS and EAE CNS tissues, that CysC contributes to cytokine and chemokine production by mixed glial cells enriched in astrocytes, and that these CysC-impacted secretory factors can promote cytokine production by CD4⁺ T cells in vitro. Thus, CysC expression in astrocytes contributes to activation of these glial cells.