Peripheral Administration of Tumor Necrosis Factor-Alpha Induces Neuroinflammation and Sickness but Not Depressive-Like Behavior in Mice.
Clinical observations indicate that activation of the TNF-α system may contribute to the development of inflammation-associated depression. Here, we tested the hypothesis that systemic upregulation of TNF-α induces neuroinflammation and behavioral changes relevant to depression. We report that a single intraperitoneal injection of TNF-α in mice increased serum and brain levels of the proinflammatory mediators TNF-α, IL-6, and MCP-1, in a dose- and time-dependent manner, but not IL-1β. Protein levels of the anti-inflammatory cytokine IL-10 increased in serum but not in the brain. The transient release of immune molecules was followed by glial cell activation as indicated by increased astrocyte activation in bioluminescent Gfap-luc mice and elevated immunoreactivity against the microglial marker Iba1 in the dentate gyrus of TNF-α-challenged mice. Additionally, TNF-α-injected mice were evaluated in a panel of behavioral tests commonly used to study sickness and depressive-like behavior in rodents. Our behavioral data imply that systemic administration of TNF-α induces a strong sickness response characterized by reduced locomotor activity, decreased fluid intake, and body weight loss. Depressive-like behavior could not be separated from sickness at any of the time points studied. Together, these results demonstrate that peripheral TNF-α affects the central nervous system at a neuroimmune and behavioral level.
BIOMED, Hasselt University, Agoralaan C Building, 3590 Diepenbeek, Belgium ; Neurosciences, Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
Steven
S
Biesmans
Neurosciences, Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
Jan A
JA
Bouwknecht
Neurosciences, Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
Luc
L
Ver Donck
Neurosciences, Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
Xavier
X
Langlois
Molecular Imaging, Janssen Research & Development LLC, Welsh & McKean Roads, Spring House, PA 19477-0779, USA.
Paul D
PD
Acton
Neurosciences, Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
Patrick
P
De Haes
BIOMED, Hasselt University, Agoralaan C Building, 3590 Diepenbeek, Belgium ; Neurosciences, Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
Nima
N
Davoodi
BIOMED, Hasselt University, Agoralaan C Building, 3590 Diepenbeek, Belgium ; Neurosciences, Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
Theo F
TF
Meert
BIOMED, Hasselt University, Agoralaan C Building, 3590 Diepenbeek, Belgium.
Niels
N
Hellings
Neurosciences, Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
Rony
R
Nuydens
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D003863:Depression / Q000378:metabolism / Q000473:pathology; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects* / Q000494:pharmacology
C491049:Aif1 protein, mouse; D015415:Biomarkers; D002135:Calcium-Binding Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C556062:IL10 protein, mouse; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D008840:Microfilament Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10