Defective Autophagy in T Cells Impairs the Development of Diet-Induced Hepatic Steatosis and Atherosclerosis

Abstract

Macroautophagy (or autophagy) is a conserved cellular process in which cytoplasmic cargo is targeted for lysosomal degradation. Autophagy is crucial for the functional integrity of different subsets of T cells in various developmental stages. Since atherosclerosis is an inflammatory disease of the vessel wall which is partly characterized by T cell mediated autoimmunity, we investigated how advanced atherosclerotic lesions develop in mice with T cells that lack autophagy-related protein 7 (Atg7), a protein required for functional autophagy. Mice with a T cell-specific knock-out of Atg7 (Lck-Cre Atg7f/f) had a diminished naïve CD4+ and CD8+ T cell compartment in the spleen and mediastinal lymph node as compared to littermate controls (Atg7f/f). Lck-Cre Atg7f/f and Atg7f/f mice were injected intravenously with rAAV2/8-D377Y-mPCSK9 and fed a Western-type diet to induce atherosclerosis. While Lck-Cre Atg7f/f mice had equal serum Proprotein Convertase Subtilisin/Kexin type 9 levels as compared to Atg7f/f mice, serum cholesterol levels were significantly diminished in Lck-Cre Atg7f/f mice. Histological analysis of the liver revealed less steatosis, and liver gene expression profiling showed decreased expression of genes associated with hepatic steatosis in Lck-Cre Atg7f/f mice as compared to Atg7f/f mice. The level of hepatic CD4+ and CD8+ T cells was greatly diminished but both CD4+ and CD8+ T cells showed a relative increase in their IFNγ and IL-17 production upon Atg7 deficiency. Atg7 deficiency furthermore reduced the hepatic NKT cell population which was decreased to < 0.1% of the lymphocyte population. Interestingly, T cell-specific knock-out of Atg7 decreased the mean atherosclerotic lesion size in the tri-valve area by over 50%. Taken together, T cell-specific deficiency of Atg7 resulted in a decrease in hepatic steatosis and limited inflammatory potency in the (naïve) T cell compartment in peripheral lymphoid tissues, which was associated with a strong reduction in experimental atherosclerosis.

IRGM/Irgm1 Aggravates Progression of Atherosclerosis by Inducing Macrophage Apoptosis through the MAPK Signaling Pathway

“…In previous studies, IRGM/Irgm1 was found to play a critical role in IFN-γ-induced autophagy (41,42). It has been reported that IRGM/Irgm1 can promote macrophage autophagy and inhibit the activation of inflammasome NLRP3, thereby protecting the intestine from inflammatory attack (39,43).…”

“…The pioneer of atherosclerotic inflammation theory, Peter Libby, pointed out very early that inflammation starts from the recruitment of white blood cells and secretion of proinflammatory factors in the early stage of atherosclerosis and is involved in the entire process of the disease (36). The CANTOS study published in 2017 revealed that the administration of IL-1β monoclonal antibody canakinumab could provide a significant In previous studies, IRGM/Irgm1 was found to play a critical role in IFN-γ-induced autophagy (41,42). It has been reported that IRGM/Irgm1 can promote macrophage autophagy and inhibit the activation of inflammasome NLRP3, thereby protecting the intestine from inflammatory attack (39,43).…”

“…Hunn et al . have shown that IRGM belongs to the family of interferon-induced GTPases (IRGs), genetically and functionally related to proteins implicated in chronic inflammatory diseases (38–39). Therefore, we analyzed expression of serum IRGM in patients with STEMI and found that serum IRGM was significantly increased in the RUP group (Figure 1B).…”

Autophagy in T Cell Function and Aging

“…In a model of inflammatory bowel disease, mice bearing ATG16L1-deficient T cells develop a more severe disease with increased T helper (Th)2 differentiation and reduced regulatory T cell (Treg) generation, with no major alterations on Th1 and Th17 populations (Kabat et al, 2016). On the other hand, in a mouse model of diet induced steatosis, ATG7-deficient T cells show increased expression of IFN ɣ and IL-17 in both CD4+ and CD8+ T cells, suggesting differentiation bias toward Th1 and Th17 phenotypes in CD4+ T cells (Amersfoort et al, 2018). Furthermore, through regulated degradation of the transcription factor PU.1, autophagy has also been shown to limit Th9 differentiation, and T cells deficient in ATG3 or ATG5 show increased IL-9 production and improved IL-9-mediated tumor control (Rivera Vargas et al, 2017).…”

Impaired Autophagy in CD11b + Dendritic Cells Expands CD4 + Regulatory T Cells and Limits Atherosclerosis in Mice

“…A recent study reported decreased atherosclerosis in mice with autophagy-related protein ( Atg7 ) deletion in T cells. 10 The atheroprotective effect could not be attributed to a reduction of T-cell–mediated inflammation because Atg7 -deficient T cells produced higher levels of the proatherogenic IFN (interferon)-γ. Htowever, Atg7 deficiency in T cells was associated with an unexplained reduction of plasma cholesterol levels, which may have accounted for the atheroprotective effects. Given that dysfunctional autophagy may impair T helper cell differentiation, effector cell activation 11 and anergy, 12 memory formation, 13 as well as regulatory T-cell (Treg) responses, 14 addressing the role of autophagy in selective T-cell subsets is necessary for a better understanding of the relevance of those processes to atherogenesis.…”