Fractalkine modulates TNF-? secretion and neurotoxicity induced by microglial activation

Abstract

Among the chemokine family, fractalkine shows unusual properties: it exists as a membrane‐bound and soluble protein, and both fractalkine and its receptor CX3CR1 are expressed predominantly in the central nervous system. In rat cell culture models, the chemokine fractalkine was expressed in neurons and microglia, but not in astrocytes and its receptor exclusively localized to microglial cells, where its expression was downregulated by treatment with the bacterial endotoxin (LPS). In microglial cultures, LPS (10 ng/ml) induced a marked increase in the release of the proinflammatory cytokine tumor necrosis factor‐α (TNF‐α). The effects of LPS on TNF‐α secretion were partially blocked (30%) by fractalkine and the effects of fractalkine were reversed by a polyclonal anti‐fractalkine antibody. When microglial‐associated fractalkine was neutralized by anti‐fractalkine antibody, the LPS response was increased by 80%, suggesting tonic activation of microglial fractalkine receptors by endogenous fractalkine. The effects of the antibody were antagonized by the addition of fractalkine. LPS‐activated microglia were neurotoxic when added to neuronal hippocampal culture, producing 20% neuronal death, as measured by NeuN‐positive cell counting. An anti‐fractalkine antibody produced neurotoxic effects of similar magnitude in this co‐culture system and also markedly potentiated the neurotoxic effects of LPS‐activated microglia (40% neuronal death). These results suggest that endogenous fractalkine might act tonically as an anti‐inflammatory chemokine in cerebral tissue through its ability to control and suppress certain aspects of microglial activation. These data may have relevance to degenerative conditions such as multiple sclerosis, in which cerebral inflammatory processes may be activated. GLIA 29:305–315, 2000. © 2000 Wiley‐Liss, Inc.

Fractalkine/CX3CL1 production by human airway smooth muscle cells: induction by IFN-γ and TNF-α and regulation by TGF-β and corticosteroids

“…There is evidence to suggest that FKN has anti-inflammatory activity. FKN suppresses LPS-induced TNF-␣ and IL-6 secretion in microglial cultures in vitro (42,58). Furthermore, in rat models of neuroinflammation induced by cerebral injection of LPS, neutralization of endogenous brain FKN with specific antibodies was associated with potentiation of LPS-induced release of inflammatory mediators, including TNF-␣ and 8-isoprostane, a marker of oxidative stress (59).…”

“…TGF-␤ had no effect on IFN-␥-and TNF-␣-induced JNK phosphorylation [58,208.8 Ϯ 8,017.432 relative light units (RLU) vs. 57,256.8 Ϯ 7,367.463 RLU in the absence and presence of TGF-␤, n ϭ 4, P Ն 0.05]. Dexamethasone, however, had a small but significant inhibitory effect on IFN-␥-and TNF-␣-induced JNK phosphorylation (58,208.750 Ϯ 8,017.432 RLU vs. 46,811 Ϯ 6,183.3 RLU in the absence and presence of dexamethasone, n ϭ 4, P Յ 0.05). TGF-␤ and dexamethasone had no direct effect on JNK phosphorylation, and the total protein content of JNK remained unchanged under all treatment conditions (data not shown).…”

Chemokines and Chemokine Receptors in Neurological Disease: Raise, Retain, or Reduce?

“…A protective and anti-inflammatory role of CX3CL1 has also been suggested in AD. 85,86 Cardona et al, 87 using three different in vivo models, also showed that the inhibition of CX3CR1 dysregulates microglial responses resulting in neurotoxicity. These data suggest preferentially a protective role of CX3CL1-CX3CR1 signaling, and raise concerns that CNS penetration by CX3CR1 antagonists might increase neuronal vulnerability.…”

Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes

“…83 In addition to increasing phagocytosis, FKN has also been associated with anti-inflammatory actions such as providing neuroprotection during glutamate toxicity, 84,85 modulating TNF-α secretion by microglia, 86 and promoting proliferative effects, 87,88 which may all have important roles in different settings of cell clearance. However, clarification is needed as to which processed form is responsible for these FKN effects.…”