The type 1 TNF receptor and its associated adapter protein, FAN, are required for TNFα-induced sickness behavior

Rationale During the course of an infection, the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) acts in the brain to trigger development of behavioral responses, collectively termed sickness behavior. Biological activities of TNFα can be mediated by TNF receptor type 1 (TNF-R1) and type 2 (TNF-R2). TNFα activates neutral sphingomyelinase through the TNF-R1 adapter protein FAN (factor associated with neutral sphingomyelinase activation), but a behavioral role of FAN in the brain has never been reported. Objectives We hypothesized that TNFα-induced sickness behavior requires TNF-R1 and that FAN is a necessary component for this response. Materials and methods We determined the role of brain TNF-R1 in sickness behavior by administering an optimal amount of TNFα intracerebroventricularly (i.c.v., 50 ng/mouse) to wild-type (WT), TNF-R1-, TNF-R2-, and FAN-deficient mice. Sickness was assessed by decreased social exploration of a novel juvenile, induction of immobility, and loss of body weight. Results TNF-R1-deficient mice were resistant to the sickness-inducing properties of i.c.v. TNFα, whereas both TNF-R2-deficient and WT mice were fully responsive. Furthermore, the complete absence of TNFα-induced sickness behavior in FAN-deficient mice provided in vivo evidence that FAN-dependent TNF-R1 signaling is critical for this central action of TNFα. Conclusions This is the first report to demonstrate that TNFα-induced sickness behavior is fully mediated by TNF-R1 and that the adaptor protein FAN is a necessary intracellular intermediate for sickness behavior.