Pathogenic and Protective Functions of TNF in Neuroinflammation Are Defined by Its Expression in T Lymphocytes and Myeloid Cells
- 1 December 2011
- journal article
- Published by The American Association of Immunologists
- Vol. 187 (11), 5660-5670
- https://doi.org/10.4049/jimmunol.1100663
Abstract
TNF displays pathogenic activities in many autoimmune disorders. However, anti-TNF therapy in multiple sclerosis patients failed because of poorly understood reasons. We used a panel of gene-targeted mice that allowed cell-type specific ablation of TNF to uncover pathogenic and protective contributions of this cytokine during autoimmune disease of the CNS. T cells and myeloid cells were found to be critical cellular sources of TNF during experimental autoimmune encephalomyelitis (EAE). TNF produced by myeloid cells accelerated the onset of disease by regulation of chemokine expression in the CNS, driving the recruitment of inflammatory cells into the target organ. TNF produced by T cells exacerbated the damage to the CNS during EAE by regulating infiltration of inflammatory myeloid cells into the CNS. In secondary lymphoid organs, TNF expressed by myeloid cells and T cells acted in synergy to dampen IL-12p40 and IL-6 production by APCs, subsequently inhibiting the development of encephalitogenic T cell responses of Th1 and Th17 types. This dual role of TNF during EAE (protective in lymphoid organs and pathogenic in CNS) suggests that global TNF blockade might be inefficient in multiple sclerosis patients because augmented autoreactive T cell development in lymphoid tissues might overwhelm the beneficial effects resulting from TNF inhibition in the CNS.Keywords
This publication has 45 references indexed in Scilit:
- RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammationNature Immunology, 2011
- Cellular source and molecular form of TNF specify its distinct functions in organization of secondary lymphoid organsBlood, 2010
- Astrocyte-Restricted Ablation of Interleukin-17-Induced Act1-Mediated Signaling Ameliorates Autoimmune EncephalomyelitisImmunity, 2010
- Inflammatory cytokines stimulate the chemokines CCL2/MCP-1 and CCL7/MCP-7 through NFκB and MAPK dependent pathways in rat astrocytesBrain Research, 2009
- IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in miceJCI Insight, 2008
- Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cellsThe Journal of Experimental Medicine, 2008
- IL-12– and IL-23–modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibitionThe Journal of Experimental Medicine, 2008
- Structure–function relationships in the IL-17 receptor: Implications for signal transduction and therapyCytokine, 2008
- Loss of blood–brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse modelsProceedings of the National Academy of Sciences of the United States of America, 2007
- Signalling pathways of the TNF superfamily: a double-edged swordNature Reviews Immunology, 2003