Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 9, Pages 3731-3736Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1011774108
Keywords
cytokines; antiinflammatory therapy
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Funding
- Deutsche Forschungsgemeinschaft [FG 661/TP4, SPP1468]
- Bundesministerium fur Bildung und Forschung [01EM0514, 01GQ0731, 0314102]
- Ankyloss and Immunopain
- European Union
- University of Erlangen-Nuremberg
- Doerenkamp Professor for Innovations in Animal and Consumer Protection
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There has been a consistent gap in understanding how TNF-alpha neutralization affects the disease state of arthritis patients so rapidly, considering that joint inflammation in rheumatoid arthritis is a chronic condition with structural changes. We thus hypothesized that neutralization of TNF-alpha acts through the CNS before directly affecting joint inflammation. Through use of functional MRI (fMRI), we demonstrate that within 24 h after neutralization of TNF-alpha, nociceptive CNS activity in the thalamus and somatosensoric cortex, but also the activation of the limbic system, is blocked. Brain areas showing blood-oxygen level-dependent signals, a validated method to assess neuronal activity elicited by pain, were significantly reduced as early as 24 h after an infusion of a monoclonal antibody to TNF-alpha. In contrast, clinical and laboratory markers of inflammation, such as joint swelling and acute phase reactants, were not affected by anti-TNF-alpha at these early time points. Moreover, arthritic mice over-expressing human TNF-alpha showed an altered pain behavior and a more intensive, widespread, and prolonged brain activity upon nociceptive stimuli compared with wild-type mice. Similar to humans, these changes, as well as the rewiring of CNS activity resulting in tight clustering in the thalamus, were rapidly reversed after neutralization of TNF-alpha. These results suggest that neutralization of TNF-alpha affects nociceptive brain activity in the context of arthritis, long before it achieves anti-inflammatory effects in the joints.
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