Transforming growth factor beta-activated kinase 1 (TAK1)-dependent checkpoint in the survival of dendritic cells promotes immune homeostasis and function

Abstract

Homeostatic control of dendritic cell (DC) survival is crucial for adaptive immunity, but the molecular mechanism is not well defined. Moreover, how DCs influence immune homeostasis under steady state remains unclear. Combining DC-specific and -inducible deletion systems, we report that transforming growth factor betaactivated kinase 1 (TAK1) is an essential regulator of DC survival and immune system homeostasis and function. Deficiency of TAK1 in CD11c + cells induced markedly elevated apoptosis, leading to the depletion of DC populations, especially the CD8 + and CD103 + DC subsets in lymphoid and nonlymphoid tissues, respectively. TAK1 also contributed to DC development by promoting the generation of DC precursors. Prosurvival signals from Toll-like receptors, CD40 and receptor activator of nuclear factor-κB (RANK) are integrated by TAK1 in DCs, which in turn mediated activation of downstream NF-κB and AKT-Foxo pathways and established a gene-expression program. TAK1 deficiency in DCs caused a myeloid proliferative disorder characterized by expansion of neutrophils and inflammatory monocytes, disrupted T-cell homeostasis, and prevented effective T-cell priming and generation of regulatory T cells. Moreover, TAK1 signaling in DCs was required to prevent myeloid proliferation even in the absence of lymphocytes, indicating a previously unappreciated regulatory mechanism of DC-mediated control of myeloid cell-dependent inflammation. Therefore, TAK1 orchestrates a prosurvival checkpoint in DCs that affects the homeostasis and function of the immune system. innate immunity | immune tolerance

Transforming Growth Factor-β–Activated Kinase 1 Regulates Angiogenesis via AMP-Activated Protein Kinase-α1 and Redox Balance in Endothelial Cells

“…21 The deletion of both TAK1 and AMPKα1 attenuated SOD2 expression in endothelial cells, and both kinases have been reported previously to target nuclear factor κB 6 and Forkhead box class O. 30,41 There are strong links between SOD2 activity and angiogenesis as the mitochondrial generation of H 2 O 2 by SOD2 has been reported previously to promote endothelial cell sprouting. Moreover, SOD2 overexpression increases H 2 O 2 -dependent blood vessel formation in the chicken chorioallantoic membrane.…”

“…TAK1 has been referred to as the most widely used MAP kinase kinase kinase in the immune system 29 and regulates the activity of several kinase pathways, including the nuclear factor κB and Akt pathways 30 in addition to that of the AMPK. TAK1 is probably best linked to inflammation, which is closely linked to angiogenesis.…”

Deficiency of Autophagy in Dendritic Cells Protects against Experimental Autoimmune Encephalomyelitis

“…Cre-mediated gene deletion is often incomplete (26,27). Moreover, there are many subsets of DCs, and CD11c-cre-mediated gene deletion has been shown to be incomplete in plasmacytoid DCs (28). Plasmacytoid DCs play a major role in priming of T cells during EAE (29).…”

Tuberous sclerosis 1 (Tsc1)-dependent metabolic checkpoint controls development of dendritic cells

“…Flow cytometry was performed as described previously (61,62). For intracellular cytokine detection, cells were stimulated for 5 h with PMA and ionomycin in the presence of monensin before staining, according to the manufacturer's instructions (BD Biosciences Following incubation, cells were collected, washed twice with PBS, and lysed in 0.5% (vol/vol) Triton X-100.…”

“…The cycling threshold value of the endogenous control gene (HPRT or actin) was subtracted from the cycling threshold value of each target gene to generate the change in cycling threshold (ΔCT). The relative expression of each target gene is expressed as the fold change relative to that of WT samples (2 −ΔΔCT ), as described (61,62), and the values of biological replicates are presented. Immunoblotting was performed as described (61,62) using the following antibodies: p-S6, p70 S6K (p-S6K), p-AKT (Ser473), p-4EBP1, Myc (all from Cell Signaling Technology), Bcl-2 (Santa Cruz), Bim (Abcam), Puma, and β-actin (both from Sigma).…”