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

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Abstract

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.

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Acknowledgments

This research was supported by grants from the National Institutes of Health to K.W.K. (MH 51569 and AG 029573) and R.D. (MH 071349). The authors gratefully acknowledge Caroline Nevoit for her excellent technical assistance.

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Authors and Affiliations

  1. Integrative Immunology and Behavior Program, Laboratory of Integrative Immunophysiology, Departments of Animal Sciences and Pathology, University of Illinois at Urbana-Champaign, 227 Edward R. Madigan Laboratory, 1201 West Gregory Drive, Urbana, IL, 61801-3873, USA

    Robert Dantzer & Keith W. Kelley

  2. Integrative Neurobiology, CNRS-INRA-University Victor Segalen, Bordeaux, France

    Rose-Marie Bluthé & Françoise Moos

  3. INSERM U 466, Institut Louis Bugnard, CHU Rangueil, Toulouse, France

    Thierry Levade

  4. Integrative Immunology and Behavior Program, Laboratory of Integrative Immunophysiology, Department of Animal Sciences, University of Illinois at Urbana-Champaign, 227 Edward R. Madigan Laboratory, 1201 West Gregory Drive, Urbana, IL 61801-3873, USA

    Karine Palin & Robert H. McCusker

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  1. Karine Palin
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  2. Rose-Marie Bluthé
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  3. Robert H. McCusker
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  4. Thierry Levade
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  5. Françoise Moos
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  6. Robert Dantzer
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  7. Keith W. Kelley
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Corresponding author

Correspondence to Keith W. Kelley.

Electronic supplementary material

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213_2008_1331_MOESM1_ESM.doc

Supplemental material Table S1. Body weight change induced by i.c.v. injection of TNFα in mice. Body weight change 6 h after treatment in the experiment described above was analyzed by a one-way ANOVA. As expected, body weight was significantly reduced 6 h following i.c.v. injection of TNFα as compared to the aCSF treatment [F(3, 20) = 19.6, p < 0.001; Supporting information table S1). Post hoc comparisons of individual dose means revealed no difference in body weight loss among the three doses of TNFα. (DOC 37.5 KB)

213_2008_1331_MOESM2_ESM.pdf

Supplemental material Figure S1. Centrally injected TNFα at 50 ng induces all the major symptoms of sickness behavior in mice. A. Duration of social exploration. B. Duration of immobility. Mice were treated i.c.v. with 1 μl of either aCSF or TNFα (three concentrations of 25, 50, or 100 ng/μl), and features of sickness behavior were measured over a 3-min duration at time 0 and 2, 6, and 24 h post-treatment. Twenty-four mice were allocated to four i.c.v. treatment groups per treatment matched for mean baseline social exploration time and body weight. Duration of exploration and immobility were analyzed by a two-way ANOVA with treatment (aCSF, TNFα 25, TNFα 50, and TNFα 100) as a between-subject factor and time (0, 2, 6, and 24 h) as a within-subject factor. The baseline for duration of social exploration ranged from 87 ± 9 to 93 ± 4 s over the four treatments (time 0; Supporting information Fig. S1A). Duration of social exploration was affected by treatments in a time-dependent manner [dose × time interaction; F(9, 60) = 4.1, p < 0.01]. Post hoc comparisons of individual group means revealed that TNFα decreased the duration of social exploration for 25 ng at only 6 h (p < 0.05), for 50 ng at both 2 (p < 0.05) and at 6 h (p < 0.001), and for 100 ng at both 2 (p < 0.05) and at 6 h (p < 0.05). Social exploration returned to control levels by 24 h for all TNFα groups. At initiation of the experiment, all mice were fully active. Duration of immobility increased in response to TNFα according to time [dose × time interaction; F(6, 40) = 3.2, p < 0.01; Supporting information Fig. S1B]. Post hoc comparisons of individual group means revealed that TNFα increased immobility for 25 ng at 2 and 6 h (p < 0.05) and both 50 and 100 ng at 2, 6, and 24 h (p < 0.05). Based upon results of this experiment, we selected a dose of 50 ng TNFα for subsequent experiments, since this concentration was able to induce the full spectrum of sickness behavior symptoms for the duration of the test. Each value represents the mean ± SEM. (n = 6/group; *p < 0.05 and § p < 0.01 compared to the aCSF control at each time). (PDF 132 KB)

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Palin, K., Bluthé, RM., McCusker, R.H. et al. The type 1 TNF receptor and its associated adapter protein, FAN, are required for TNFα-induced sickness behavior. Psychopharmacology 201, 549–556 (2009). https://doi.org/10.1007/s00213-008-1331-4

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