PT  - JOURNAL ARTICLE
AU  - Xi Chen
AU  - Jianjun Chang
AU  - Qiudong Deng
AU  - Jie Xu
AU  - Thi A. Nguyen
AU  - Lauren H. Martens
AU  - Basar Cenik
AU  - Georgia Taylor
AU  - Kathryn F. Hudson
AU  - Jaegwon Chung
AU  - Kimberley Yu
AU  - Phillip Yu
AU  - Joachim Herz
AU  - Robert V. Farese, Jr.
AU  - Thomas Kukar
AU  - Malú G. Tansey
TI  - 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
AID  - 10.1523/JNEUROSCI.5336-12.2013
DP  - 2013 May 22
TA  - The Journal of Neuroscience
PG  - 9202--9213
VI  - 33
IP  - 21
4099  - http://www.jneurosci.org/content/33/21/9202.short
4100  - http://www.jneurosci.org/content/33/21/9202.full
SO  - J. Neurosci.2013 May 22; 33
AB  - 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.