PMID- 28182011
OWN - NLM
STAT- MEDLINE
DCOM- 20171031
LR  - 20210109
IS  - 2041-4889 (Electronic)
VI  - 8
IP  - 2
DP  - 2017 Feb 9
TI  - TAK1 regulates resident macrophages by protecting lysosomal integrity.
PG  - e2598
LID - 10.1038/cddis.2017.23 [doi]
AB  - Hematopoietic cell survival and death is critical for development of a functional 
      immune system. Here, we report that a protein kinase, TAK1, is selectively 
      required for resident macrophage integrity during embryogenesis. Hematopoietic 
      lineage-specific deletion of Tak1 gene (Tak1(HKO)) caused accumulation of 
      cellular debris in the thymus in perinatal mice. Although no overt alteration in 
      thymocytes and blood myeloid populations was observed in Tak1(HKO) mice, we found 
      that thymic and lung macrophages were diminished. In the in vitro setting, Tak1 
      deficiency caused profound disruption of lysosomes and killed bone marrow-derived 
      macrophages (BMDMs) without any exogenous stressors. Inhibition of the lysosomal 
      protease, cathepsin B, partially blocked Tak1-deficient BMDM death, suggesting 
      that leakage of the lysosomal contents is in part the cause of cell death. To 
      identify the trigger of this cell death, we examined involvement of TNF and 
      Toll-like receptor pathways. Among them, we found that deletion of Tnfr1 
      partially rescued cell death. Finally, we show that Tnfr1 deletion partially 
      restored thymic and lung macrophages in vivo. These results suggest that 
      autocrine and potentially paracrine TNF kills Tak1-deficient macrophages during 
      development. Our results reveal that TAK1 signaling maintains proper macrophage 
      populations through protecting lysosomal integrity.
FAU - Sakamachi, Yosuke
AU  - Sakamachi Y
AD  - Department of Biological Sciences, North Carolina State University, Raleigh, NC 
      27695-7633, USA.
FAU - Morioka, Sho
AU  - Morioka S
AD  - Department of Biological Sciences, North Carolina State University, Raleigh, NC 
      27695-7633, USA.
FAU - Mihaly, September R
AU  - Mihaly SR
AD  - Department of Biological Sciences, North Carolina State University, Raleigh, NC 
      27695-7633, USA.
FAU - Takaesu, Giichi
AU  - Takaesu G
AD  - Department of Biological Sciences, North Carolina State University, Raleigh, NC 
      27695-7633, USA.
FAU - Foley, Julie F
AU  - Foley JF
AD  - Cellular and Molecular Pathology Branch, National Institute of Environmental 
      Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, 
      USA.
FAU - Fessler, Michael B
AU  - Fessler MB
AD  - Immunity, Inflammation and Disease Laboratory, National Institute of 
      Environmental Health Sciences, National Institute of Health, Research Triangle 
      Park, NC 27709, USA.
FAU - Ninomiya-Tsuji, Jun
AU  - Ninomiya-Tsuji J
AUID- ORCID: 0000-0002-5584-0176
AD  - Department of Biological Sciences, North Carolina State University, Raleigh, NC 
      27695-7633, USA.
LA  - eng
GR  - R01 GM068812/GM/NIGMS NIH HHS/United States
GR  - R01 GM112986/GM/NIGMS NIH HHS/United States
GR  - T32 ES007046/ES/NIEHS NIH HHS/United States
GR  - Z01 ES102005/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
DEP - 20170209
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Protective Agents)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type I)
RN  - 0 (Toll-Like Receptors)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
RN  - EC 2.7.11.25 (MAP kinase kinase kinase 7)
SB  - IM
MH  - Animals
MH  - Cell Death/physiology
MH  - Cell Survival/physiology
MH  - Embryonic Development/physiology
MH  - Lung/metabolism
MH  - Lysosomes/*metabolism
MH  - MAP Kinase Kinase Kinases/*metabolism
MH  - Macrophages/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Protective Agents/*metabolism
MH  - Receptors, Tumor Necrosis Factor, Type I/metabolism
MH  - Signal Transduction/physiology
MH  - Thymocytes/physiology
MH  - Thymus Gland/metabolism
MH  - Toll-Like Receptors/metabolism
PMC - PMC5386472
COIS- The authors declare no conflict of interest.
EDAT- 2017/02/10 06:00
MHDA- 2017/11/01 06:00
PMCR- 2017/02/01
CRDT- 2017/02/10 06:00
PHST- 2016/12/07 00:00 [received]
PHST- 2017/01/04 00:00 [accepted]
PHST- 2017/02/10 06:00 [entrez]
PHST- 2017/02/10 06:00 [pubmed]
PHST- 2017/11/01 06:00 [medline]
PHST- 2017/02/01 00:00 [pmc-release]
AID - cddis201723 [pii]
AID - 10.1038/cddis.2017.23 [doi]
PST - epublish
SO  - Cell Death Dis. 2017 Feb 9;8(2):e2598. doi: 10.1038/cddis.2017.23.