HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance

Nature Communications, Aug 2014

Proinflammatory cytokines play important roles in insulin resistance. Here we report that mice with a T-cell-specific conditional knockout of HGK (T-HGK cKO) develop systemic inflammation and insulin resistance. This condition is ameliorated by either IL-6 or IL-17 neutralization. HGK directly phosphorylates TRAF2, leading to its lysosomal degradation and subsequent inhibition of IL-6 production. IL-6-overproducing HGK-deficient T cells accumulate in adipose tissue and further differentiate into IL-6/IL-17 double-positive cells. Moreover, CCL20 neutralization or CCR6 deficiency reduces the Th17 population or insulin resistance in T-HGK cKO mice. In addition, leptin receptor deficiency in T cells inhibits Th17 differentiation and improves the insulin sensitivity in T-HGK cKO mice, which suggests that leptin cooperates with IL-6 to promote Th17 differentiation. Thus, HGK deficiency induces TRAF2/IL-6 upregulation, leading to IL-6/leptin-induced Th17 differentiation in adipose tissue and subsequent insulin resistance. These findings provide insight into the reciprocal regulation between the immune system and the metabolism.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://www.nature.com/articles/ncomms5602.pdf

HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance

Abstract Proinflammatory cytokines play important roles in insulin resistance. Here we report that mice with a T-cell-specific conditional knockout of HGK (T-HGK cKO) develop systemic inflammation and insulin resistance. This condition is ameliorated by either IL-6 or IL-17 neutralization. HGK directly phosphorylates TRAF2, leading to its lysosomal degradation and subsequent inhibition of IL-6 production. IL-6-overproducing HGK-deficient T cells accumulate in adipose tissue and further differentiate into IL-6/IL-17 double-positive cells. Moreover, CCL20 neutralization or CCR6 deficiency reduces the Th17 population or insulin resistance in T-HGK cKO mice. In addition, leptin receptor deficiency in T cells inhibits Th17 differentiation and improves the insulin sensitivity in T-HGK cKO mice, which suggests that leptin cooperates with IL-6 to promote Th17 differentiation. Thus, HGK deficiency induces TRAF2/IL-6 upregulation, leading to IL-6/leptin-induced Th17 differentiation in adipose tissue and subsequent insulin resistance. These findings provide insight into the reciprocal regulation between the immune system and the metabolism. Introduction T-helper 17 (Th17) cells, a subset of T-helper (CD4+) cells, mainly produce interleukin (IL)-17, IL-17F, IL-21 and IL-22. IL-6-, IL-21- or IL-23-induced STAT3 (signal transducer and activator of transcription 3) activation facilitates Th17 differentiation1,2. IL-6 stimulation induces IL-21 production and an IL-21 self-amplifying loop; IL-23 further helps expansion and stabilization of Th17 population1,2. Conversely, the transforming growth factor-β (TGF-β)-Smad pathway limits Th1 and Th2 differentiation through downregulation of T-bet/GATA-3 expression, leading to increased Th17 differentiation. The recruitment of Th17 cells to different tissues is mediated by CCL20 and CCL22, along with their respective cognate chemokine receptors CCR6 and CCR4 (refs 3, 4). The proinflammatory cytokines IL-17 and IL-22 secreted by infiltrating Th17 cells can cause tissue damages2. Th17 cells are involved in many autoimmune diseases or inflammatory diseases, such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease and type 2 diabetes (T2D)5,6,7. HPK1/GCK-like kinase (HGK), also named MAP4K4 (mitogen-actiavted protein kinase kinase kinase kinase 4), is a kinase that belongs to the mammalian Ste20-like family of serine/threonine kinases8. Whole-body HGK-deficient mice show early embryonic lethality9, implicating that HGK has an important function in embryonic development. Earlier studies using cultured cells show that HGK has various cellular functions. Tumour necrosis factor-α (TNF-α)-stimulated HGK induces JNK (c-Jun N-terminal kinase) activation through MKK4 and MKK7 in 293T cells8, while HGK inhibits adipose lipogenesis in an AMPK- and mammalian target of rapamycin-dependent but JNK-independent pathway10. HGK also impairs insulin signalling/glucose uptake in adipocytes and skeletal muscle cells, leading to insulin resistance11,12. Moreover, HGK protects pancreatic β-cells from the reduction of insulin secretion by TNF-α13. HGK small interfering RNA knockdown in murine macrophages inhibits lipopolysaccharide-induced septic shock by downregulating IL-1β and TNF-α production14. In addition, HGK has been identified as a promigratory kinase by a small interfering RNA screening15. Consistently, HGK expression is also associated with worse prognosis of pancreatic ductal adenocarcinoma, colorectal cancer and lung adenocarcinoma16,17,18. Recent report also shows that the interaction of HGK with Pyk2 contributes to glioma cell migration19. Taken together, HGK is involved in multiple physiological functions in different cell types. Our previous studies indicate that two other MAP4K family kinases, HPK1 (MAP4K1)20 and GLK (MAP4K3)21, play important roles in T-cell receptor signalling and T-cell-mediated immune responses22,23. To date, the roles of HGK in lymphocyte signalling have not been investigated. In this report, we studied the in vivo roles of HGK in T-cell signalling and immune regulation by generating T-cell-specific HGK conditional knockout (T-HGK cKO) mice. We found that HGK downregulates IL-6 production in T cells through direct phosphorylation and degradation of TNF receptor-associated factor 2 (TRAF2), leading to the suppression of Th17 cell-mediated insulin resistance. Results T-HGK cKO mice show inflammation-associated disorders The specific deletion of HGK in T cells from T-HGK cKO mice (Fig. 1a) was confirmed by immunoblotting analyses (Fig. 1b). T-HGK cKO mice displayed normal development of T cells, B cells, neutrophils and macrophages (Fig. 1c and Supplementary Fig. 1a,b), as well as normal development and function of Treg cells (Fig. 1d and Supplementary Fig. 1c,d). T-HGK cKO mice showed severe dermatitis and cataracts starting between 12 and 23 weeks of age. These mice also showed hepatosplenomegaly, alo (...truncated)


This is a preview of a remote PDF: https://www.nature.com/articles/ncomms5602.pdf

Huai-Chia Chuang, Wayne H. -H. Sheu, Yi-Ting Lin, Ching-Yi Tsai, Chia-Yu Yang, Yu-Jhen Cheng, Pau-Yi Huang, Ju-Pi Li, Li-Li Chiu, Xiaohong Wang, Min Xie, Michael D. Schneider, Tse-Hua Tan. HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance, Nature Communications, 2014, Issue: 5, DOI: 10.1038/ncomms5602