OX40 Regulates Both Innate and Adaptive Immunity and Promotes Nonalcoholic Steatohepatitis

Sun, Guan; Jin, Hua; Zhang, Chunpan; Meng, Hua; Zhao, Xinyan; Wei, Dan; Ou, Xiaojuan; Wang, Qianyi; Li, Shuxiang; Wang, Tianqi; Sun, Xiaojing; Shi, Wei; Tian, Dan; Liu, Kai; Xu, Huji; Tian, Yue; Li, Xinmin; Guo, Wei; Jia, Jidong; Zhang, Zhongtao; Zhang, Dong

doi:10.1016/j.celrep.2018.12.006

Cited by 42 publications

(47 citation statements)

References 46 publications

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“…In this respect, a study from 2018 (reF. 95 ) has shed some light on the involvement of OX40 (CD134) in NASH. OX40 is a costimulatory molecule of the TNF family that is largely expressed on activated T cells in both mice and humans 96 .…”

Section: Mechanisms Promoting Adaptive Immunitymentioning

confidence: 99%

“…Upon ligation by OX40 ligand (OX40L, CD252) which is present on APCs, OX40 promotes T cell responses 96 . In mice receiving a high-fat diet, OX40 and OX40L are upregulated in the livers of mice with NASH, and OX40 deficiency selectively lowers hepatic CD4 + T cell recruitment and T H 1 and T H 17 cell differentiation, ameliorating steatosis, and reducing the release of alanine aminotransferase and aspartate aminotransferase and the prevalence of M1 macrophages 95 . Interestingly, levels of soluble OX40 are also increased in the plasma of patients with NASH, positively correlating with the severity of steatohepatitis 95 .…”

Section: Mechanisms Promoting Adaptive Immunitymentioning

confidence: 99%

“…In mice receiving a high-fat diet, OX40 and OX40L are upregulated in the livers of mice with NASH, and OX40 deficiency selectively lowers hepatic CD4 + T cell recruitment and T H 1 and T H 17 cell differentiation, ameliorating steatosis, and reducing the release of alanine aminotransferase and aspartate aminotransferase and the prevalence of M1 macrophages 95 . Interestingly, levels of soluble OX40 are also increased in the plasma of patients with NASH, positively correlating with the severity of steatohepatitis 95 . These data, along with the observation that OX40 promotes insulin resistance and obesity-induced CD4 + T cell responses in VAT 97 , suggest that OX40 and possibly other costimulatory molecules can critically influence adaptive immunity in NASH.…”

Section: Mechanisms Promoting Adaptive Immunitymentioning

confidence: 99%

“…However, the overall picture is still quite confused owing to conflicting results. For instance, despite the association of CD4 + T H 1 and T H 17 cells with NASH inflammatory mechanisms 27,33,35,[41][42][43][44]95 , one study has shown that the selective depletion of CD4 + T cells accelerates HCC growth when NASH is induced in mice with hepatocyte-specific overexpression of MYC 113 . In these animals, CD4 + T cell loss has been ascribed to mitochondrial oxidative stress resulting from disrupted lipid metabolism 113 .…”

Section: Mechanisms Promoting Adaptive Immunitymentioning

confidence: 99%

“…In these animals, CD4 + T cell loss has been ascribed to mitochondrial oxidative stress resulting from disrupted lipid metabolism 113 . However, how these data relate to the expansion of CD4 + T cells observed in many different models of NASH 27,33,35,[41][42][43][44]95 , and how CD4 + T cell depletion can favour tumour growth, is not clear.…”

Section: Mechanisms Promoting Adaptive Immunitymentioning

confidence: 99%

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Adaptive immunity: an emerging player in the progression of NAFLD

Sutti

Albano

2019

Nat Rev Gastroenterol Hepatol

263

245

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In the past decade, nonalcoholic fatty liver disease (NAFLD) has become a leading cause of chronic liver disease and cirrhosis, as well as an important risk factor for hepatocellular carcinoma (HCC). NAFLD encompasses a spectrum of liver lesions, including simple steatosis, steatohepatitis and fibrosis. Although steatosis is often harmless, the lobular inflammation that characterizes nonalcoholic steatohepatitis (NASH) is considered a driving force in the progression of NAFLD. The current view is that innate immune mechanisms represent a key element in supporting hepatic inflammation in NASH. However, increasing evidence points to the role of adaptive immunity as an additional factor promoting liver inflammation. This Review discusses data regarding the role of B cells and T cells in sustaining the progression of NASH to fibrosis and HCC, along with the findings that antigens originating from oxidative stress act as a trigger for immune responses. We also highlight the mechanisms affecting liver immune tolerance in the setting of steatohepatitis that favour lymphocyte activation. Finally , we analyse emerging evidence concerning the possible application of immune modulating treatments in NASH therapy.

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Section: Mechanisms Promoting Adaptive Immunitymentioning

confidence: 99%

Section: Mechanisms Promoting Adaptive Immunitymentioning

confidence: 99%

Section: Mechanisms Promoting Adaptive Immunitymentioning

confidence: 99%

Section: Mechanisms Promoting Adaptive Immunitymentioning

confidence: 99%

Section: Mechanisms Promoting Adaptive Immunitymentioning

confidence: 99%

See 3 more Smart Citations

Adaptive immunity: an emerging player in the progression of NAFLD

Sutti

Albano

2019

Nat Rev Gastroenterol Hepatol

263

245

View full text Add to dashboard Cite

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T cells: Friends and foes in NASH pathogenesis and hepatocarcinogenesis

2022

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In association with the pandemic spreading of obesity and metabolic syndrome, the prevalence of NAFLD-related HCC is increasing almost exponentially. In recent years, many of the underlining multifactorial causes of NAFLD have been identified, and the cellular mechanisms sustaining disease development have been dissected up to the single-cell level. However, there is still an urgent need to provide clinicians with more therapeutic targets, with particular attention on NAFLD-induced HCC, where immune checkpoint inhibitors do not work as efficiently. Whereas much effort has been invested in elucidating the role of innate immune response in the hepatic NAFLD microenvironment, only in the past decade have novel critical roles been unraveled for T cells in driving chronic inflammation toward HCC. The metabolic and immune microenvironment interact to recreate a tumor-promoting and immune-suppressive terrain, responsible for resistance to anticancer therapy.In this article, we will review the specific functions of several T-cell populations involved in NAFLD and NAFLD-driven HCC. We will illustrate the cellular crosstalk with other immune cells, regulatory networks or stimulatory effects of these interactions, and role of the metabolic microenvironment in influencing immune cell functionality. Finally, we will present the pros and cons of the current therapeutic strategies against NAFLD-related HCC and delineate possible novel approaches for the future.

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Decoding the role of immune T cells: A new territory for improvement of metabolic‐associated fatty liver disease

Liu

Ding

Bai

et al. 2023

iMeta

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Metabolic-associated fatty liver disease (MAFLD) is a new emerging concept and is associated with metabolic dysfunction, generally replacing the name of nonalcoholic fatty liver disease (NAFLD) due to heterogeneous liver condition and inaccuracies in definition. The prevalence of MAFLD is rising by year due to dietary changes, metabolic disorders, and no approved therapy, affecting a quarter of the global population and representing a major economic problem that burdens healthcare systems. Currently, in addition to the common causative factors like insulin resistance, oxidative stress, and lipotoxicity, the role of immune cells, especially T cells, played in MAFLD is increasingly being emphasized by global scholars. Based on the diverse classification and pathophysiological effects of immune T cells, we comprehensively analyzed their bidirectional regulatory effects on the hepatic inflammatory microenvironment and MAFLD progression. This interaction between MAFLD and T cells was also associated with hepatic-intestinal immune crosstalk and gut microbiota homeostasis. Moreover, we pointed out several T-cell-based therapeutic approaches including but not limited to adoptive transfer of T cells, fecal microbiota transplantation, and drug therapy, especially for natural products and Chinese herbal prescriptions. Overall, this study contributes to a better understanding of the important role of T cells played in MAFLD progression and corresponding therapeutic options and provides a potential reference for further drug development.

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OX40 Regulates Both Innate and Adaptive Immunity and Promotes Nonalcoholic Steatohepatitis

Cited by 42 publications

References 46 publications

Adaptive immunity: an emerging player in the progression of NAFLD

Adaptive immunity: an emerging player in the progression of NAFLD

T cells: Friends and foes in NASH pathogenesis and hepatocarcinogenesis

Decoding the role of immune T cells: A new territory for improvement of metabolic‐associated fatty liver disease

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