Minna Yli-Karjanmaa1, Kathrine Solevad Larsen1, Christina Dühring Fenger1, Lotte Kellemann Kristensen1, Nellie Anne Martin1, Peter Toft Jensen1, Alexandre Breton2, Lubov Nathanson3, Pernille Vinther Nielsen1, Minna Christiansen Lund1, Stephanie Lindeman Carlsen1, Jan Bert Gramsbergen1, Bente Finsen4, Jane Stubbe5, Lars Henrik Frich6, Helen Stolp7, Roberta Brambilla8, Daniel Clive Anthony9, Morten Meyer4, Kate Lykke Lambertsen10. 1. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. 2. Department of Pharmacology, University of Oxford, Oxford, UK. 3. Institute for Neuro Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA. 4. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; BRIDGE - Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark. 5. Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. 6. Orthopedic Research Unit, Department of Clinical Research, University of Southern Denmark, Odense, Denmark. 7. Department of Pharmacology, University of Oxford, Oxford, UK; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK. 8. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; BRIDGE - Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark; The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA. 9. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; Department of Pharmacology, University of Oxford, Oxford, UK; BRIDGE - Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark. 10. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; BRIDGE - Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Department of Neurology, Odense University Hospital, Odense, Denmark. Electronic address: klambertsen@health.sdu.dk.
Abstract
BACKGROUND: Although tumor necrosis factor (TNF) inhibitors are used to treat chronic inflammatory diseases, there is little information about how long-term inhibition of TNF affects the homeostatic functions that TNF maintains in the intact CNS. MATERIALS AND METHODS: To assess whether developmental TNF deficiency causes alterations in the naïve CNS, we estimated the number of proliferating cells, microglia, and neurons in the developing neocortex of E13.5, P7 and adult TNF knock out (TNF-/-) mice and wildtype (WT) littermates. We also measured changes in gene and protein expression and monoamine levels in adult WT and TNF-/- mice. To evaluate long-term effects of TNF inhibitors, we treated healthy adult C57BL/6 mice with either saline, the selective soluble TNF inhibitor XPro1595, or the nonselective TNF inhibitor etanercept. We estimated changes in cell number and protein expression after two months of treatment. We assessed the effects of TNF deficiency on cognition by testing adult WT and TNF-/- mice and mice treated with saline, XPro1595, or etanercept with specific behavioral tasks. RESULTS: TNF deficiency decreased the number of proliferating cells and microglia and increased the number of neurons. At the same time, TNF deficiency decreased the expression of WNT signaling-related proteins, specifically Collagen Triple Helix Repeat Containing 1 (CTHRC1) and Frizzled receptor 6 (FZD6). In contrast to XPro1595, long-term inhibition of TNF with etanercept in adult C57BL/6 mice decreased the number of BrdU+ cells in the granule cell layer of the dentate gyrus. Etanercept, but not XPro1595, also impaired spatial learning and memory in the Barnes maze memory test. CONCLUSION: TNF deficiency impacts the organization of neurogenic zones and alters the cell composition in brain. Long-term inhibition of TNF with the nonselective TNF inhibitor etanercept, but not the soluble TNF inhibitor XPro1595, decreases neurogenesis in the adult mouse hippocampus and impairs learning and memory after two months of treatment.
BACKGROUND: Although tumor necrosis factor (TNF) inhibitors are used to treat chronic inflammatory diseases, there is little information about how long-term inhibition of TNF affects the homeostatic functions that TNF maintains in the intact CNS. MATERIALS AND METHODS: To assess whether developmental TNF deficiency causes alterations in the naïve CNS, we estimated the number of proliferating cells, microglia, and neurons in the developing neocortex of E13.5, P7 and adult TNF knock out (TNF-/-) mice and wildtype (WT) littermates. We also measured changes in gene and protein expression and monoamine levels in adult WT and TNF-/- mice. To evaluate long-term effects of TNF inhibitors, we treated healthy adult C57BL/6 mice with either saline, the selective soluble TNF inhibitor XPro1595, or the nonselective TNF inhibitor etanercept. We estimated changes in cell number and protein expression after two months of treatment. We assessed the effects of TNF deficiency on cognition by testing adult WT and TNF-/- mice and mice treated with saline, XPro1595, or etanercept with specific behavioral tasks. RESULTS:TNF deficiency decreased the number of proliferating cells and microglia and increased the number of neurons. At the same time, TNF deficiency decreased the expression of WNT signaling-related proteins, specifically Collagen Triple Helix Repeat Containing 1 (CTHRC1) and Frizzled receptor 6 (FZD6). In contrast to XPro1595, long-term inhibition of TNF with etanercept in adult C57BL/6 mice decreased the number of BrdU+ cells in the granule cell layer of the dentate gyrus. Etanercept, but not XPro1595, also impaired spatial learning and memory in the Barnes maze memory test. CONCLUSION:TNF deficiency impacts the organization of neurogenic zones and alters the cell composition in brain. Long-term inhibition of TNF with the nonselective TNF inhibitor etanercept, but not the soluble TNF inhibitor XPro1595, decreases neurogenesis in the adult mouse hippocampus and impairs learning and memory after two months of treatment.
Authors: Harald Hampel; Filippo Caraci; A Claudio Cuello; Giuseppe Caruso; Robert Nisticò; Massimo Corbo; Filippo Baldacci; Nicola Toschi; Francesco Garaci; Patrizia A Chiesa; Steven R Verdooner; Leyla Akman-Anderson; Félix Hernández; Jesús Ávila; Enzo Emanuele; Pedro L Valenzuela; Alejandro Lucía; Mark Watling; Bruno P Imbimbo; Andrea Vergallo; Simone Lista Journal: Front Immunol Date: 2020-03-31 Impact factor: 7.561
Authors: Ira S Rostevanov; Batya Betesh-Abay; Ahmad Nassar; Elina Rubin; Sarit Uzzan; Jacob Kaplanski; Linoy Biton; Abed N Azab Journal: Front Immunol Date: 2022-09-06 Impact factor: 8.786
Authors: Marcus Augusto-Oliveira; Gabriela P Arrifano; Amanda Lopes-Araújo; Leticia Santos-Sacramento; Priscila Y Takeda; Daniel C Anthony; João O Malva; Maria Elena Crespo-Lopez Journal: Cells Date: 2019-10-22 Impact factor: 6.600