TAK1 regulates resident macrophages by protecting lysosomal integrity.
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 (Tak1HKO) caused accumulation of cellular debris in the thymus in perinatal mice. Although no overt alteration in thymocytes and blood myeloid populations was observed in Tak1HKOmice, 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.
Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7633, USA.
Yosuke
Y
Sakamachi
Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7633, USA.
Sho
S
Morioka
Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7633, USA.
September R
SR
Mihaly
Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7633, USA.
Giichi
G
Takaesu
Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Julie F
JF
Foley
Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709, USA.
Michael B
MB
Fessler
Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7633, USA.
Jun
0000-0002-5584-0176
J
Ninomiya-Tsuji
D000818:Animals; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D047108:Embryonic Development / Q000502:physiology; D008168:Lung / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020011:Protective Agents / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D060168:Thymocytes / Q000502:physiology; D013950:Thymus Gland / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D020930:MAP Kinase Kinase Kinases; D020011:Protective Agents; D047888:Receptors, Tumor Necrosis Factor, Type I; D051193:Toll-Like Receptors; D000099151:MAP Kinase Kinase Kinase 7