Immunocompetent astrocytes and microglia display major differences in the processing of the invariant chain and in the expression of active cathepsin L and cathepsin S

Abstract

The role of astrocytes and microglia as antigen‐presenting cells in the brain is still controversial. In this study we have analyzed and compared aspects of the molecular machinery that underlies MHC class II trafficking in immunocompetent astrocytes and microglia. We show that IFN‐γ‐stimulated microglia possess active cathepsin L and cathepsin S, and efficiently degrade the invariant chain, unlike IFN‐γ‐stimulated astrocytes that express cathepsin L but not cathepsin S. The lack of cathepsin S proves to be dramatic for the antigen‐presentation capacity of astrocytes, whichis nearly abolished when these cells are stimulated by a combination of IFN‐γ and TNF‐α. TNF‐α indeed decreases cathepsin L activity as we show here, leading to alterations in invariantchain processing, and hence in MHC class II trafficking in astrocytes. Cystatin C inhibits cathepsin L activity in astrocytes, but does not regulate cathepsin L and cathepsin S activity in microglia. We therefore identify cathepsin L and cathepsin S as key components in the regulation of the immune potential of astrocytes and microglia, and provide evidence for a cell‐specific regulation exerted byIFN‐γ and TNF‐α on the expression and activity of cathepsins.

Common host genes are activated in mouse brain by Japanese encephalitis and rabies viruses

“…Cathepsin S, a lysosomal cysteine protease, is involved in the processing of MHC class II-associated invariant chain in interferon-c-stimulated microglia (Gresser et al, 2001). Recently, cathepsins were shown to be involved in virus disassembly as well (Ebert et al, 2002).…”

Cathepsin L Acutely Alters Microvessel Integrity within the Neurovascular Unit during Focal Cerebral Ischemia

“…27 Cathepsin L production has been attributed to neurons, microglia, astrocytes, fibroblasts from various origins, and other cell types. [28][29][30] These experiments confirm that cysteine protease activity generated acutely during focal ischemia in the striatum is predominantly cathepsin L, not cathepsin B, which responds much later ( Figure 1). 2 LG3 fragment from purified perlecan was significantly greater by activities secreted from microglia subject to OGD (filled bars) than by normoxia (open bars) (n = 6 per condition pooled from three independent experiments; P = 0.0043).…”

“…These are under modulation by tumor necrosis factor-α and interferon-γ, 30 cytokines also generated during focal cerebral ischemia. 35 In Tissue samples were incubated with microglia-conditioned medium ex vivo at 37°C for 2 hours and then processed for immunoblots.…”

Use of Cystatin C Determination in Clinical Diagnostics

“…In the brain it probably inhibits astrocytic activity of cathepsin L which together with cathepsin S are to key components for regulation of the immune potential of astrocytes and microglia 22 . Patients with this disease have very low concentrations of cystatin C in the CSF as well as systemic circulation.…”