Progranulin does not bind tumor necrosis factor (TNF) receptors and is not a direct regulator of TNF-dependent signaling or bioactivity in immune or neuronal cells

Xi Chen, Jianjun Chang, Qiudong Deng, Jie Xu, Thi A. Nguyen, Lauren H. Martens, Basar Cenik, Georgia Taylor, Kathryn F. Hudson, Jaegwon Chung, Kimberley Yu, Phillip Yu, Joachim Herz, Robert V. Farese, Thomas Kukar, Malú G. Tansey

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Abstract

Progranulin (PGRN) is a secreted glycoprotein expressed in neurons and glia that is implicated in neuronal survival on the basis that mutations in the GRN gene causing haploinsufficiency result in a familial form of frontotemporal dementia (FTD). Recently, a direct interaction between PGRN and tumor necrosis factor receptors (TNFR I/II) was reported and proposed to be a mechanism by which PGRN exerts anti-inflammatory activity, raising the possibility that aberrant PGRN-TNFR interactions underlie the molecular basis for neuroinflammation in frontotemporal lobar degeneration pathogenesis. Here, we report that we find no evidence for a direct physical or functional interaction between PGRN and TNFRs. Using coimmunoprecipitation and surface plasmon resonance (SPR) we replicated the interaction between PGRN and sortilin and that between TNF and TNFRI/II, but not the interaction between PGRN and TNFRs. Recombinant PGRN or transfection of a cDNA encoding PGRN did not antagonize TNF-dependent NFκB, Akt, and Erk1/2 pathway activation; inflammatory gene expression; or secretion of inflammatory factors in BV2 microglia and bone marrow-derived macrophages (BMDMs). Moreover, PGRN did not antagonize TNF-induced cytotoxicity on dopaminergic neuroblastoma cells. Last, co-addition or pre-incubation with various N-or C-terminal-tagged recombinant PGRNs did not alter lipopolysaccharide-induced inflammatory gene expression or cytokine secretion in any cell type examined, including BMDMs from Grn+/-or Grn-/-mice. Therefore, the neuroinflammatory phenotype associated with PGRN deficiency in the CNS is not a direct consequence of the loss of TNF antagonism by PGRN, but may be a secondary response by glia to disrupted interactions between PGRN and Sortilin and/or other binding partners yet to be identified.

Original languageEnglish (US)
Pages (from-to)9202-9213
Number of pages12
JournalJournal of Neuroscience
Volume33
Issue number21
DOIs
StatePublished - May 22 2013

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Tumor Necrosis Factor Receptors
Tumor Necrosis Factor-alpha
Neuroglia
Macrophages
Frontotemporal Lobar Degeneration
Receptors, Tumor Necrosis Factor, Type I
Gene Expression
Haploinsufficiency
Frontotemporal Dementia
Surface Plasmon Resonance
Microglia
Neuroblastoma
Transfection
Lipopolysaccharides
Glycoproteins
Anti-Inflammatory Agents
Complementary DNA
Cytokines
Phenotype
Neurons

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Progranulin does not bind tumor necrosis factor (TNF) receptors and is not a direct regulator of TNF-dependent signaling or bioactivity in immune or neuronal cells. / Chen, Xi; Chang, Jianjun; Deng, Qiudong; Xu, Jie; Nguyen, Thi A.; Martens, Lauren H.; Cenik, Basar; Taylor, Georgia; Hudson, Kathryn F.; Chung, Jaegwon; Yu, Kimberley; Yu, Phillip; Herz, Joachim; Farese, Robert V.; Kukar, Thomas; Tansey, Malú G.

In: Journal of Neuroscience, Vol. 33, No. 21, 22.05.2013, p. 9202-9213.

Research output: Contribution to journalArticle

Chen, X, Chang, J, Deng, Q, Xu, J, Nguyen, TA, Martens, LH, Cenik, B, Taylor, G, Hudson, KF, Chung, J, Yu, K, Yu, P, Herz, J, Farese, RV, Kukar, T & Tansey, MG 2013, 'Progranulin does not bind tumor necrosis factor (TNF) receptors and is not a direct regulator of TNF-dependent signaling or bioactivity in immune or neuronal cells', Journal of Neuroscience, vol. 33, no. 21, pp. 9202-9213. https://doi.org/10.1523/JNEUROSCI.5336-12.2013
Chen, Xi ; Chang, Jianjun ; Deng, Qiudong ; Xu, Jie ; Nguyen, Thi A. ; Martens, Lauren H. ; Cenik, Basar ; Taylor, Georgia ; Hudson, Kathryn F. ; Chung, Jaegwon ; Yu, Kimberley ; Yu, Phillip ; Herz, Joachim ; Farese, Robert V. ; Kukar, Thomas ; Tansey, Malú G. / Progranulin does not bind tumor necrosis factor (TNF) receptors and is not a direct regulator of TNF-dependent signaling or bioactivity in immune or neuronal cells. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 21. pp. 9202-9213.
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abstract = "Progranulin (PGRN) is a secreted glycoprotein expressed in neurons and glia that is implicated in neuronal survival on the basis that mutations in the GRN gene causing haploinsufficiency result in a familial form of frontotemporal dementia (FTD). Recently, a direct interaction between PGRN and tumor necrosis factor receptors (TNFR I/II) was reported and proposed to be a mechanism by which PGRN exerts anti-inflammatory activity, raising the possibility that aberrant PGRN-TNFR interactions underlie the molecular basis for neuroinflammation in frontotemporal lobar degeneration pathogenesis. Here, we report that we find no evidence for a direct physical or functional interaction between PGRN and TNFRs. Using coimmunoprecipitation and surface plasmon resonance (SPR) we replicated the interaction between PGRN and sortilin and that between TNF and TNFRI/II, but not the interaction between PGRN and TNFRs. Recombinant PGRN or transfection of a cDNA encoding PGRN did not antagonize TNF-dependent NFκB, Akt, and Erk1/2 pathway activation; inflammatory gene expression; or secretion of inflammatory factors in BV2 microglia and bone marrow-derived macrophages (BMDMs). Moreover, PGRN did not antagonize TNF-induced cytotoxicity on dopaminergic neuroblastoma cells. Last, co-addition or pre-incubation with various N-or C-terminal-tagged recombinant PGRNs did not alter lipopolysaccharide-induced inflammatory gene expression or cytokine secretion in any cell type examined, including BMDMs from Grn+/-or Grn-/-mice. Therefore, the neuroinflammatory phenotype associated with PGRN deficiency in the CNS is not a direct consequence of the loss of TNF antagonism by PGRN, but may be a secondary response by glia to disrupted interactions between PGRN and Sortilin and/or other binding partners yet to be identified.",
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AU - Chen, Xi

AU - Chang, Jianjun

AU - Deng, Qiudong

AU - Xu, Jie

AU - Nguyen, Thi A.

AU - Martens, Lauren H.

AU - Cenik, Basar

AU - Taylor, Georgia

AU - Hudson, Kathryn F.

AU - Chung, Jaegwon

AU - Yu, Kimberley

AU - Yu, Phillip

AU - Herz, Joachim

AU - Farese, Robert V.

AU - Kukar, Thomas

AU - Tansey, Malú G.

PY - 2013/5/22

Y1 - 2013/5/22

N2 - Progranulin (PGRN) is a secreted glycoprotein expressed in neurons and glia that is implicated in neuronal survival on the basis that mutations in the GRN gene causing haploinsufficiency result in a familial form of frontotemporal dementia (FTD). Recently, a direct interaction between PGRN and tumor necrosis factor receptors (TNFR I/II) was reported and proposed to be a mechanism by which PGRN exerts anti-inflammatory activity, raising the possibility that aberrant PGRN-TNFR interactions underlie the molecular basis for neuroinflammation in frontotemporal lobar degeneration pathogenesis. Here, we report that we find no evidence for a direct physical or functional interaction between PGRN and TNFRs. Using coimmunoprecipitation and surface plasmon resonance (SPR) we replicated the interaction between PGRN and sortilin and that between TNF and TNFRI/II, but not the interaction between PGRN and TNFRs. Recombinant PGRN or transfection of a cDNA encoding PGRN did not antagonize TNF-dependent NFκB, Akt, and Erk1/2 pathway activation; inflammatory gene expression; or secretion of inflammatory factors in BV2 microglia and bone marrow-derived macrophages (BMDMs). Moreover, PGRN did not antagonize TNF-induced cytotoxicity on dopaminergic neuroblastoma cells. Last, co-addition or pre-incubation with various N-or C-terminal-tagged recombinant PGRNs did not alter lipopolysaccharide-induced inflammatory gene expression or cytokine secretion in any cell type examined, including BMDMs from Grn+/-or Grn-/-mice. Therefore, the neuroinflammatory phenotype associated with PGRN deficiency in the CNS is not a direct consequence of the loss of TNF antagonism by PGRN, but may be a secondary response by glia to disrupted interactions between PGRN and Sortilin and/or other binding partners yet to be identified.

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