Activation of invariant natural killer T cells by alpha-galactosylceramide ameliorates doxorubicin-induced cardiotoxicity in mice

Obata, Yuki; Ishimori, Naoki; Saito, Akimichi; Kinugawa, Shintaro; Yokota, Takashi; Takada, Shingo; Nakano, Ikuo; Kakutani, Naoya; Yamanashi, Katsuma; Anzai, Toshihisa

doi:10.1177/2047487319901208

Cited by 11 publications

(15 citation statements)

References 10 publications

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“…A qPCR analysis revealed that M2 macrophage expression was higher in mice treated with Dox+ αGC mice than in mice with Dox only. In this study, it was concluded that iNKT cell activation prevented Dox-induced LV dysfunction and cardiac fibrosis in mouse hearts hinting at a role for these cells in Dox-induced cardiotoxicity [ 103 ].…”

Section: Dox-induced Cardiomyocyte Injurymentioning

confidence: 99%

The Innate Immune System in Cardiovascular Diseases and Its Role in Doxorubicin-Induced Cardiotoxicity

Bhagat

Shrestha

Kleinerman

2022

IJMS

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Innate immune cells are the early responders to infection and tissue damage. They play a critical role in the initiation and resolution of inflammation in response to insult as well as tissue repair. Following ischemic or non-ischemic cardiac injury, a strong inflammatory response plays a critical role in the removal of cell debris and tissue remodeling. However, persistent inflammation could be detrimental to the heart. Studies suggest that cardiac inflammation and tissue repair needs to be tightly regulated such that the timely resolution of the inflammation may prevent adverse cardiac damage. This involves the recognition of damage; activation and release of soluble mediators such as cytokines, chemokines, and proteases; and immune cells such as monocytes, macrophages, and neutrophils. This is important in the context of doxorubicin-induced cardiotoxicity as well. Doxorubicin (Dox) is an effective chemotherapy against multiple cancers but at the cost of cardiotoxicity. The innate immune system has emerged as a contributor to exacerbate the disease. In this review, we discuss the current understanding of the role of innate immunity in the pathogenesis of cardiovascular disease and dox-induced cardiotoxicity and provide potential therapeutic targets to alleviate the damage.

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Section: Dox-induced Cardiomyocyte Injurymentioning

confidence: 99%

The Innate Immune System in Cardiovascular Diseases and Its Role in Doxorubicin-Induced Cardiotoxicity

Bhagat

Shrestha

Kleinerman

2022

IJMS

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“…four times greater than in those without CHF (3)(4)(5)(6). Conversely, cancer patients can be at increased risk of cardiac disease due to deterioration of their lifestyle behaviors (e.g., inactivity and an unbalanced diet) (7), and also due to treatment toxicity, as many anticancer drugs are known to cause cardiotoxic side effects (8)(9)(10)(11). Therefore, cancer and cardiovascular diseases can be mutual disease drivers, and hence co-occur frequently in patients (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Cross-disease communication between cancer and heart failure provides a rational approach to prevention and treatment of both diseases

Takada

Kinugawa²,

Handa³

et al. 2022

Front. Oncol.

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Accumulating clinical data have demonstrated a clear positive association between cancer and cardiac disorders, particularly chronic heart failure (CHF). These two diseases can be mutual drivers of each other, and hence frequently co-occur in patients. The immune system is the core mechanism that eliminates transformed cells from our bodies. However, immune cells often play distinct or even conflicting roles in cancer and CHF. Moreover, CHF alters the properties of immune cells, particularly those of regulatory T cells. Our previous study showed that the oxidative phosphorylation capacity of peripheral blood mononuclear cells is impaired in CHF, leading to the increased production of reactive oxygen species. Therefore, the co-occurrence of cancer and CHF becomes a serious problem, affecting the treatment of both diseases, and consequently negatively affecting patient survival rates. To date, few methods have been identified that effectively treat both diseases at the same time. Mitochondria activity may change in immune cells during their activation and exhaustion, and in CHF. Mitochondria activity is also largely affected in myocardia in CHF. We here focus on the mitochondrial abnormalities of immune cells in cancer and CHF, and discuss possible ways to treat cancer and CHF at the same time by targeting mitochondrial abnormalities. Many cancer cells are inevitably produced daily in our bodies, mostly owing to enzymatic nucleotide errors of DNA replication and repair. Therefore, the possibility of ways to prevent cancer by preventing the onset of heart failure will also be discussed.

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“…NKT cells, with common characteristics of T cells and natural killer cells, are an indispensable part of the liver immune system 8,9 . As the main undertaker of inheriting the function of NKT cells, invariant NKT (iNKT) cells can recognize the lipid antigens presented by CD1d, and after being activated, secrete a series of cytokines, thus participating in the regulation of innate and adaptive immunity 10,11,12 . A typical example is that iNKT cells are rapidly activated by the stimulation of α-galactosylceramide (α-GalCer) and secrete a large number of Th1 and Th2 cytokines to participate in the immune response 13,14 .…”

Section: Introductionmentioning

confidence: 99%

“…A typical example is that iNKT cells are rapidly activated by the stimulation of α-galactosylceramide (α-GalCer) and secrete a large number of Th1 and Th2 cytokines to participate in the immune response 13,14 . In addition, iNKT cells can interact with other immune cells in a cell-to-cell manner to regulate host immunity 12 . Moreover, in immune-related liver diseases, iNKT cells play important roles in regulating liver immune homeostasis and disease pathogenesis 15,16 .…”

Section: Introductionmentioning

confidence: 99%

UGCG relieves iNKT cell-mediated liver injury by triggering endoplasmic reticulum stress in mice

Gan

Mao

et al. 2022

Preprint

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Immune-mediated liver injury is associated with excessive activation of invariant natural killer T (iNKT) cells, and the role and regulatory mechanisms of UDP-glucosylceramide glucosyltransferase (UGCG) in iNKT cell-mediated liver injury remain poorly defined. Here, we report UGCG induced endoplasmic reticulum (ER) stress, which is beneficial for hepatocytes to resist injury caused by iNKT cells, thereby improving immune-mediated liver injury outcomes in mice. UGCG levels were elevated in mice treated with concanavalin A, with excessive activation of iNKT cells. However, after UGCG inhibition, liver injury were alleviated along with reduced activation of iNKT cells. Interestingly, hepatocytes showed marked autophagy upon inhibition of UGCG. Mechanistically, inhibition of UGCG caused an increase in glucose-regulated protein 78, LC3B-II/LC3B-I ratio and phosphorylated NF-κB p65, thereby triggering ER stress-mediated autophagy. These findings showed ER stress links UGCG with hepatic autophagy.

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Activation of invariant natural killer T cells by alpha-galactosylceramide ameliorates doxorubicin-induced cardiotoxicity in mice

Cited by 11 publications

References 10 publications

The Innate Immune System in Cardiovascular Diseases and Its Role in Doxorubicin-Induced Cardiotoxicity

The Innate Immune System in Cardiovascular Diseases and Its Role in Doxorubicin-Induced Cardiotoxicity

Cross-disease communication between cancer and heart failure provides a rational approach to prevention and treatment of both diseases

UGCG relieves iNKT cell-mediated liver injury by triggering endoplasmic reticulum stress in mice

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