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Microglia and the urokinase plasminogen activator receptor/uPA system in innate brain inflammation
Author(s) -
Cunningham Orla,
Campion Suzanne,
Perry V. Hugh,
Murray Carol,
Sidenius Nicolai,
Docagne Fabian,
Cunningham Colm
Publication year - 2009
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20892
Subject(s) - urokinase receptor , biology , plasmin , neurodegeneration , inflammation , plasminogen activator , microglia , tissue plasminogen activator , central nervous system , cancer research , microbiology and biotechnology , immunology , pathology , endocrinology , medicine , biochemistry , disease , enzyme
The urokinase plasminogen activator (uPA) receptor (uPAR) is a GPI‐linked cell surface protein that facilitates focused plasmin proteolytic activity at the cell surface. uPAR has been detected in macrophages infiltrating the central nervous system (CNS) and soluble uPAR has been detected in the cerebrospinal fluid during a number of CNS pathologies. However, its expression by resident microglial cells in vivo remains uncertain. In this work, we aimed to elucidate the murine CNS expression of uPAR and uPA as well as that of tissue plasminogen activator and plasminogen activator inhibitor 1 (PAI‐1) during insults generating distinct and well‐characterized inflammatory responses; acute intracerebral lipopolysaccharide (LPS), acute kainate‐induced neurodegeneration, and chronic neurodegeneration induced by prion disease inoculation. All three insults induced marked expression of uPAR at both mRNA and protein level compared to controls (naïve, saline, or control inoculum‐injected). uPAR expression was microglial in all cases. Conversely, uPA transcription and activity was only markedly increased during chronic neurodegeneration. Dissociation of uPA and uPAR levels in acute challenges is suggestive of additional proteolysis‐independent roles for uPAR. PAI‐1 was most highly expressed upon LPS challenge, whereas tissue plasminogen activator mRNA was constitutively present and less responsive to all insults studied. These data are novel and suggest much wider involvement of the uPAR/uPA system in CNS function and pathology than previously supposed. © 2009 Wiley‐Liss, Inc.