TNF-α receptor 1 deficiency reduces antigen-presenting capacity of Schwann cells and ameliorates experimental autoimmune neuritis in mice

Mao, Xijing; Zhang, Xingmei; Zhang, Hongliang; Quezada, Hernán Concha; Mix, Eilhard; Yang, Xin; Winblad, Bengt; Adem, Abdu; Zhu, Jie

doi:10.1016/j.neulet.2009.12.045

Cited by 21 publications

(12 citation statements)

References 22 publications

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“…Previously we found conflicting results with regard to the role of TNFR1 in EAN by using TNFR1 knockout mice [24], [25]. The discrepancy has been discussed in the latter publication [25].…”

Section: Discussionmentioning

confidence: 98%

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Attenuated EAN in TNF-α Deficient Mice Is Associated with an Altered Balance of M1/M2 Macrophages

et al. 2012

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The role of tumor necrosis factor (TNF)-α and its receptors in neuroautoimmune and neuroinflammatory diseases has been controversial. On the basis of our previous studies, we hereby aimed to further clarify TNF-α’s mechanism of action and to explore the potential role of TNF-α receptor (TNFR)1 as a therapeutic target in experimental autoimmune neuritis (EAN). EAN was induced by immunization with P0 peptide 180–199 in TNF-α knockout (KO) mice and anti-TNFR1 antibodies were used to treat EAN. Particularly, the effects of TNF-α deficiency and TNFR1 blockade on macrophage functions were investigated. The onset of EAN in TNF-α KO mice was markedly later than that in wild type (WT) mice. From day 14 post immunization, the clinical signs of TNF-α KO mice were significantly milder than those of their WT counterparts. Further, we showed that the clinical severity of WT mice treated with anti-TNFR1 antibodies was less severe than that of the control WT mice receiving PBS. Nevertheless, no difference with regard to the clinical signs of EAN or inflammatory infiltration in cauda equina was seen between TNF-α KO and WT mice with EAN after blockade of TNFR1. Although TNF-α deficiency did not alter the proliferation of lymphocytes in response to either antigenic or mitogenic stimuli, it down-regulated the production of interleukin (IL)-12 and nitric oxide (NO), and enhanced the production of IL-10 in macrophages. Increased ratio of regulatory T cells (Tregs) and reduced production of interferon (IFN)-γ in cauda equina infiltrating cells, and elevated levels of IgG2b antibodies against P0 peptide 180–199 in sera were found in TNF-α KO mice with EAN. In conclusion, TNF-α deficiency attenuates EAN via altering the M1/M2 balance of macrophages.

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“…Previously we found conflicting results with regard to the role of TNFR1 in EAN by using TNFR1 knockout mice [24], [25]. The discrepancy has been discussed in the latter publication [25].…”

Section: Discussionmentioning

confidence: 98%

“…The discrepancy has been discussed in the latter publication [25]. Moreover, TNFR2 may compensate for the loss of TNFR1 roles in TNFR1 KO mice, since TNFR1 and TNFR2 are known to trigger overlapping intracellular signaling events (e.g.…”

Section: Discussionmentioning

confidence: 99%

Attenuated EAN in TNF-α Deficient Mice Is Associated with an Altered Balance of M1/M2 Macrophages

et al. 2012

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“…Therapeutically, neutralizing TNFα or its homotrimeric cell surface receptor TNFR1 has been demonstrated to ameliorate the course of EAN (Stoll et al, 1993; Bao et al, 2003). Similarly, TNFα receptor knockout mice exhibit an attenuated course of EAN (Mao et al, 2010). …”

Section: Introductionmentioning

confidence: 99%

Tumour Necrosis Factor α Enhances CCL2 and ICAM-1 Expression in Peripheral Nerve Microvascular Endoneurial Endothelial Cells

2013

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Recruitment and trafficking of autoreactive leucocytes across the BNB (blood–nerve barrier) is an early pathological insult in GBS (Guillain-Barré syndrome), an aggressive autoimmune disorder of the PNS (peripheral nervous system). Whereas the aetiology and pathogenesis of GBS remain unclear, pro-inflammatory cytokines, including TNFα (tumour necrosis factor α), are reported to be elevated early in the course of GBS and may initiate nerve injury by activating the BNB. Previously, we reported that disrupting leucocyte trafficking in vivo therapeutically attenuates the course of an established animal model of GBS. Here, PNMECs (peripheral nerve microvascular endothelial cells) that form the BNB were harvested from rat sciatic nerves, immortalized by SV40 (simian virus 40) large T antigen transduction and subsequently challenged with TNFα. Relative changes in CCL2 (chemokine ligand 2) and ICAM-1 (intercellular adhesion molecule 1) expression were determined. We report that TNFα elicits marked dose- and time-dependent increases in CCL2 and ICAM-1 mRNA and protein content and promotes secretion of functional CCL2 from immortalized and primary PNMEC cultures. TNFα-mediated secretion of CCL2 promotes, in vitro, the transendothelial migration of CCR2-expressing THP-1 monocytes. Increased CCL2 and ICAM-1 expression in response to TNFα may facilitate recruitment and trafficking of autoreactive leucocytes across the BNB in autoimmune disorders, including GBS.

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“…Early experimental studies (Stoll et al , ) demonstrate an enhanced presence of TNF‐α‐expressing macrophage infiltrates within nerve roots from rats with experimental autoimmune neuritis (EAN), an established and well‐characterized animal model of GBS (Hahn , ) . Neutralizing TNF‐α, or its homotrimeric cell surface receptor TNFR1, has been shown to ameliorate the course of EAN (Stoll et al , ; Bao et al , ) , and TNF‐α receptor knockout mice exhibit an attenuated course of EAN (Mao et al , ) . TNF‐α is now recognized as playing a pivotal role in the pathogenesis of GBS (Lu and Zhu , ) .…”

Section: Introductionmentioning

confidence: 99%

Cdc42 GTPases facilitate TNF‐α‐mediated secretion of CCL2 from peripheral nerve microvascular endoneurial endothelial cells

Langert

Zee

Stubbs

2013

J Peripheral Nervous Sys

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Trafficking of autoreactive leukocytes across the blood-nerve barrier and into peripheral nerves is an early pathological hallmark of Guillain-Barré syndrome (GBS). Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, promotes transendothelial migration by up-regulating endothelial expression of inflammatory mediators, including CCL2, a chemokine implicated in GBS. We sought to determine the mechanism by which TNF-α induces expression and secretion of CCL2 from peripheral nerve microvascular endoneurial endothelial cells (PNMECs). Expression of CCL2 mRNA and protein in quiescent PNMEC cultures was minimal. In contrast, cultures treated with TNF-α exhibited increased CCL2 mRNA and protein content, as well as protein secretion. Simvastatin significantly attenuated TNF-α induced CCL2 secretion without affecting CCL2 mRNA or protein expression. Co-incubation with geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, prevented the effect of simvastatin. By comparison, inhibiting protein isoprenylation with GGTI-298, but not FTI-277, mimicked the effect of simvastatin and significantly attenuated transendothelial migration in vitro. Inhibition of the monomeric GTPase Cdc42, but not Rac1 or RhoA-C, attenuated TNF-α mediated CCL2 secretion. TNF-α mediated trafficking of autoreactive leukocytes into peripheral nerves during GBS may proceed by a mechanism that involves Cdc42 facilitated secretion of CCL2.

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TNF-α receptor 1 deficiency reduces antigen-presenting capacity of Schwann cells and ameliorates experimental autoimmune neuritis in mice

Cited by 21 publications

References 22 publications

Attenuated EAN in TNF-α Deficient Mice Is Associated with an Altered Balance of M1/M2 Macrophages

Attenuated EAN in TNF-α Deficient Mice Is Associated with an Altered Balance of M1/M2 Macrophages

Tumour Necrosis Factor α Enhances CCL2 and ICAM-1 Expression in Peripheral Nerve Microvascular Endoneurial Endothelial Cells

Cdc42 GTPases facilitate TNF‐α‐mediated secretion of CCL2 from peripheral nerve microvascular endoneurial endothelial cells

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