Urokinase‐Type Plasminogen Activator Receptor Regulates Leukocyte Recruitment during Experimental Pneumococcal Meningitis

Abstract

Tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) have been suggested to play an important role in inflammatory diseases. Increased levels of tPA, uPA, uPA receptor (uPAR), and their inhibitor, plasminogen activator inhibitor (PAI)-1, have been found in the cerebrospinal fluid (CSF) of patients with bacterial meningitis. Here, we show that expression of tPA, uPA, uPAR, PAI-1, and PAI-2 is up-regulated during experimental pneumococcal meningitis. In uPAR-deficient mice, CSF pleocytosis was significantly attenuated 24 h after infection, compared with that in infected wild-type (wt) mice. Lack of uPAR did not influence blood-brain barrier permeability, intracranial pressure, expression of chemokines (keratinocyte-derived cytokine and macrophage inflammatory protein-2), bacterial killing, or clinical outcome. No differences in pathophysiological alterations were observed in tPA-deficient mice, compared with those in infected wt mice. These results indicate that uPAR participates in the recruitment of leukocytes to the CSF space during pneumoccal meningitis.

Chemotactic Factors in Cerebrospinal Fluid during Bacterial Meningitis

“…In contrast, CSF tissuetype plasminogen activator (tPA) levels are elevated during bacterial meningitis but do not correlate with CSF leukocyte counts (93). In line with these data, CSF pleocytosis during experimental bacterial meningitis did not differ between tPAdeficient and wild-type mice (55).…”

“…Elevated levels of uPA and uPAR were found in CSF from patients with bacterial meningitis and correlated with CSF pleocytosis (94). Furthermore, in uPAR-deficient mice, CSF pleocytosis was significantly attenuated during experimental bacterial meningitis, despite the fact that levels of KC and MIP-2 were not affected (55). In contrast, CSF tissuetype plasminogen activator (tPA) levels are elevated during bacterial meningitis but do not correlate with CSF leukocyte counts (93).…”

The urokinase-type plasminogen activator receptor is not required for skeletal muscle inflammation or regeneration

“…Previous studies using uPAR Ϫ/Ϫ mice have indicated that uPAR plays important roles in directed cell migration in several in vivo models of inflammation and infection, including peritonitis, meningitis, and pneumonia (18,28,35,39). During thioglycollate-induced peritonitis, leukocyte accumulation was impaired at early time points, but not at later time points (13,28).…”

“…Previous studies have indicated that the receptor for uPA (uPAR) plays an important role in inflammatory cell migration (18,28,35,39) and the proliferation, migration, and fusion of satellite cells (5,12,15), all of which are thought to be required for muscle repair (17,24,42). Muscle regeneration in uPA Ϫ/Ϫ mice is severely impaired, and the impaired healing is associated with a lack of macrophage accumulation following muscle injury (22,25).…”

“…uPAR null (uPAR Ϫ/Ϫ ) mice demonstrate impaired accumulation of inflammatory cells following peritonitis (28) or pulmonary infection in vivo (18,35,39). In addition, treatment of monocytes with an anti-uPAR antibody suppressed chemotaxis induced by fMLP in vitro (19), and peritoneal macrophages collected from uPAR Ϫ/Ϫ mice failed to promote plasminogen activation (7).…”