TAK1 regulates resident macrophages by protecting lysosomal integrity

Abstract

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 Tak1HKO 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.

TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation

“…Our study identified several important effector molecules driving this cell death and inflammation downstream of TAK1-inactivation and hence potential therapeutic targets. Increased cell death of TAK1-deficeint resident macrophages has also been observed in in vivo mouse models with hematopoietic specific deletion of TAK1 ( Sakamachi et al, 2017 ). Future studies will test whether similar pathways of cell death and inflammasome activation, as established in our study, are at work in these resident macrophages.…”

Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke

“…To investigate changes in the peripheral immune compartment, the spleen of the TAK1 Δ M and control mice was immunophenotyped at day 3 post-stroke. Previous studies have shown that cell type and tissue-specific TAK1 deletion increases cell death in multiple cells and tissues including hematopoietic cells, monocytes, epidermis, and intestinal epithelium [ 14 , 32 , 35 , 42 ].…”

“…Deletion of TAK1 from neutrophils and monocyte/macrophages also microglia (Additional file 3 : Figure S3), resulted in high circulating neutrophils, monocytes, and animals develop splenomegaly [ 17 ]. Tissue-specific deletion of TAK1 caused cell death in tissues including epidermis, intestinal epithelium, hepatocytes, and osteoblasts [ 32 , 42 ]. Interestingly, myeloid-specific TAK1 deletion did not induce cell death in our study, a finding also seen by others [ 17 , 30 ].…”

NPC1-mTORC1 signaling Couples Cholesterol Sensing to Organelle Homeostasis and is a Targetable Pathway in Niemann-Pick type C

“…In turn, hydrolase depletion could stem from transcriptional inhibition or from their defective trafficking to the lysosome (Kobayashi et al, 1999;Saftig and Klumperman, 2009;Sleat et al, 2013). Alternatively, it is tempting to speculate that the increased propensity of NPC lysosomes to undergo membrane damage could result in leakage of lumenal contents, including resident hydrolases, a phenomenon suggested to occur in NPC as well as other physiological and pathological contexts (Chung et al, 2016;Hämälistö et al, 2020;Maejima et al, 2013;Sakamachi et al, 2017).…”