Mitochondrial transcription factor A (Tfam) is a pro-inflammatory extracellular signaling molecule recognized by brain microglia.
Microglia represent mononuclear phagocytes in the brain and perform immune surveillance, recognizing a number of signaling molecules released from surrounding cells in both healthy and pathological situations. The microglia interact with several damage-associated molecular pattern molecules (DAMPs) and recent data indicate that mitochondrial transcription factor A (Tfam) could act as a specific DAMP in peripheral tissues. This study tested the hypothesis that extracellular Tfam induces pro-inflammatory and cytotoxic responses of the microglia. Three different types of human mononuclear phagocytes were used to model human microglia: human peripheral blood monocytes from healthy donors, human THP-1 monocytic cells, and human primary microglia obtained from autopsy samples. When combined with interferon (IFN)-γ, recombinant human Tfam (rhTfam) induced secretions that were toxic to human SH-SY5Y neuroblastoma cells in all three models. Similar cytotoxic responses were observed when THP-1 cells and human microglia were exposed to human mitochondrial proteins in the presence of IFN-γ. rhTfam alone induced expression of pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and IL-8 by THP-1 cells. This induction was further enhanced in the presence of IFN-γ. Upregulated secretion of IL-6 in response to rhTfam plus IFN-γ was confirmed in primary human microglia. Use of specific inhibitors showed that the rhTfam-induced cytotoxicity of human THP-1 cells depended partially on activation of c-Jun N-terminal kinase (JNK), but not p38 mitogen-activated protein kinase (MAPK). Overall, our data support the hypothesis that, in the human brain, Tfam could act as an intercellular signaling molecule that is recognized by the microglia to cause pro-inflammatory and cytotoxic responses.
Department of Biology, University of British Columbia Okanagan Campus, Kelowna, BC, Canada; School of Health and Exercise Sciences, University of British Columbia Okanagan Campus, Kelowna, BC, Canada.
Jonathan P
JP
Little
School of Health and Exercise Sciences, University of British Columbia Okanagan Campus, Kelowna, BC, Canada; Department of Chemistry, University of British Columbia Okanagan Campus, Kelowna, BC, Canada.
Svetlana
S
Simtchouk
Department of Biology, University of British Columbia Okanagan Campus, Kelowna, BC, Canada.
Stephanie M
SM
Schindler
Department of Biology, University of British Columbia Okanagan Campus, Kelowna, BC, Canada.
Erika B
EB
Villanueva
Department of Biology, University of British Columbia Okanagan Campus, Kelowna, BC, Canada.
Nichole E
NE
Gill
Banner Sun Health Research Institute, Sun City, AZ, USA.
Douglas G
DG
Walker
Department of Chemistry, University of British Columbia Okanagan Campus, Kelowna, BC, Canada.
Kirsten R
KR
Wolthers
Department of Biology, University of British Columbia Okanagan Campus, Kelowna, BC, Canada. Electronic address: andis.klegeris@ubc.ca.
Andis
A
Klegeris
D001921:Brain / Q000166:cytology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000633:toxicity; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism* / Q000633:toxicity; D009000:Monocytes / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism* / Q000633:toxicity
D004268:DNA-Binding Proteins; D007378:Interleukins; D024101:Mitochondrial Proteins; C499631:TFAM protein, human; D014157:Transcription Factors; D007371:Interferon-gamma
DAMPs; Glial cells; Mitochondrial proteins; Mononuclear phagocytes; Neuroinflammation; Neurotoxicity