Fibronectin is elevated in the cerebrospinal fluid of patients suffering from bacterial meningitis and enhances inflammation caused by bacterial products in primary mouse microglial cell cultures

Abstract

Toll-like receptors (TLR) play a key role in the recognition of pathogenic organisms. Fibronectin, an extracellular matrix protein, is considered a potent stimulator of the innate immune system through TLR4. In bacterial meningitis, several extracellular matrix proteins and bacterial compounds are elevated in the CSF. For this reason, we hypothesized that these molecules may jointly stimulate the innate immune system and increase neuronal damage in bacterial meningitis. Concentrations of fibronectin were elevated in the CSF of patients suffering from bacterial meningitis, but not in patients with multiple sclerosis, when compared with control patients without CSF abnormalities. In primary cultures of mouse microglial cells, co-administration of fibronectin at concentrations occurring in the CSF in bacterial meningitis (10 microg/mL) with defined TLR agonists [lipopolysaccharide (TLR4), the synthetic lipopeptide tripalmytoyl-cysteinyl-seryl-(lysyl)3-lysine (TLR2) and single-stranded unmethylated cytosine-guanosine oligodesoxynucleotide (TLR9)] led to an additive release of nitric oxide and tumor necrosis factor-alpha when compared with the release elicited by either compound alone. In conclusion, the inflammatory reaction to bacterial compounds can be aggravated by endogenous fibronectin at elevated levels during bacterial CNS infections. This additive or synergistic effect may contribute to neuronal damage during bacterial meningitis.

Toll-like receptors 2 and 4 in ischemic stroke: Outcome and therapeutic values

“…The role of cFN and HSP60 as potential endogenous ligands of TLRs (Lasarte et al, 2007) and its relationship to other diseases has been previously described (Goos et al, 2007;Methe et al, 2005). However, these studies were conducted using recombinant proteins (Lasarte et al, 2007) or selected serum (Yang et al, 2008), instead of a pool of serum from ischemic stroke patients.…”

Bacterial meningitis: an update of new treatment options

“…TLR2 recognizing lipoteichoic acids, TLR4 detecting endotoxin and pneumolysin, and TLR9 sensing unmethylated cytosine-guanosine epitopes of bacterial DNA play an established role in the pathophysiology of bacterial meningitis [180][181][182]. TLRs not only recognize pathogen structures, but also host proteins related to tissue injury, for example, oxidized host phospholipids [183], or to the increased permeability of the blood-CSF and blood-brain barrier, for example, the bloodderived protein fibrinogen [184]. Although the use of the TLR4 antagonist eritoran in patients with severe sepsis did not reduce the 28-day mortality compared to placebo [185], eritoran has recently been shown to prevent lung injury, decrease clinical symptoms, cytokine and oxidized phospholipid expression, and viral titers, and increase survival in a murine model of influenza [183].…”

Microglia in Infectious Diseases of the Central Nervous System

“…Indeed, in an in vitro coculture model, neuronal damage was shown to result, at least partially, from NO production by activated microglia and astrocytes, which was greatly attenuated by dexamethasone (Kim and Tauber 1996). Another study has shown that the co-administration of fibronectin, an extracellular matrix protein elevated in the cerebrospinal fluid (CSF) of patients suffering from bacterial meningitis, with TLR agonists led to an additive effect on NO and TNF-α production by microglia compared to either stimulus alone (Goos et al 2007). This finding suggests that the inflammatory response to pneumococci during bacterial meningitis may be exacerbated by endogenous molecules and could contribute to the pathological damage of neurons typical of infection.…”