bims-nastce 2021-09-05 papers

Semin Immunopathol. 2021 Aug 31.

Functional heterogeneity of CD4+ T cells in liver inflammation.

Franziska Muscate, Anna Woestemeier, Nicola Gagliani.

CD4+ T cells play an essential role in orchestrating adequate immunity, but their overactivity has been associated with the development of immune-mediated inflammatory diseases, including liver inflammatory diseases. These cells can be subclassified according to their maturation stage, cytokine profile, and pro or anti-inflammatory functions, i.e., functional heterogeneity. In this review, we summarize what has been discovered so far regarding the role of the different CD4+ T cell polarization states in the progression of two prominent and still different liver inflammatory diseases: non-alcoholic steatohepatitis (NASH) and autoimmune hepatitis (AIH). Finally, the potential of CD4+ T cells as a therapeutic target in both NASH and AIH is discussed.

DOI: https://doi.org/10.1007/s00281-021-00881-w

Nat Rev Endocrinol. 2021 Sep 03.

Mitochondria transported from adipocytes in extracellular vesicles.

Claire Greenhill.

DOI: https://doi.org/10.1038/s41574-021-00563-5

Immunity. 2021 Aug 26. pii: S1074-7613(21)00211-9. [Epub ahead of print]

Identification of a Kupffer cell subset capable of reverting the T cell dysfunction induced by hepatocellular priming.

Kupffer cells (KCs) are highly abundant, intravascular, liver-resident macrophages known for their scavenger and phagocytic functions. KCs can also present antigens to CD8+ T cells and promote either tolerance or effector differentiation, but the mechanisms underlying these discrepant outcomes are poorly understood. Here, we used a mouse model of hepatitis B virus (HBV) infection, in which HBV-specific naive CD8+ T cells recognizing hepatocellular antigens are driven into a state of immune dysfunction, to identify a subset of KCs (referred to as KC2) that cross-presents hepatocellular antigens upon interleukin-2 (IL-2) administration, thus improving the antiviral function of T cells. Removing MHC-I from all KCs, including KC2, or selectively depleting KC2 impaired the capacity of IL-2 to revert the T cell dysfunction induced by intrahepatic priming. In summary, by sensing IL-2 and cross-presenting hepatocellular antigens, KC2 overcome the tolerogenic potential of the hepatic microenvironment, suggesting new strategies for boosting hepatic T cell immunity.

Keywords: CD8(+) T cells; Kupffer cells; T cell dysfunction; hepatitis B virus; imaging; interleukin-2; liver; scRNA-seq; single cell; tolerance

DOI: https://doi.org/10.1016/j.immuni.2021.05.005

Exp Cell Res. 2021 Aug 27. pii: S0014-4827(21)00354-2. [Epub ahead of print] 112801

MIG/CXCL9 exacerbates the progression of metabolic-associated fatty liver disease by disrupting Treg/Th17 balance.

Lili Li, Yujia Xia, Xiaoyu Ji, Han Wang, Zerui Zhang, Panpan Lu, Qiang Ding, Deqiong Wang, Mei Liu.

CD4+CD25+ regulatory T (Treg) cells and Th17 cells play important roles in the progression of metabolic-associated fatty liver disease (MAFLD). However, the contribution of monokine induced by interferon-gamma (MIG)/CXCL9 to the Treg/Th17 imbalance in MAFLD is only partially understood. In the present study, we detected increased levels of MIG/CXCL9 and a Treg/Th17 imbalance in the setting of metabolic-associated steatohepatitis (MASH). Recombinant adeno-associated virus-mediated gene transfer and silencing of MIG/CXCL9 expression in mice alleviated MASH and increased the Treg/Th17 ratio. Furthermore, the percentage of Th17 cells, but not Treg cells, differentiated from splenic CD4+ T cells was significantly increased by administration of MIG/CXCL9. MIG/CXCL9 also promoted Th17 cell proliferation, and its effects were dose dependent. Levels of phosphorylated c-Jun N-terminal kinase (JNK) decreased dramatically when MIG/CXCL9 was inhibited in a murine MASH model. In cultured Treg cells, phosphorylated JNK levels decreased dose-dependently in response to MIG/CXCL9 inhibition, but increased in cultured Th17 cells. This effect was blocked in the presence of a JNK inhibitor. These findings underline the fundamental importance of MIG/CXCL9 in maintaining the Treg/Th17 balance in MAFLD and provide the foundations for a novel approach to preventing and treating MAFLD.

Keywords: JNK pathway; MIG/CXCL9; Th17; Treg; metabolic-associated fatty liver disease

DOI: https://doi.org/10.1016/j.yexcr.2021.112801

Trends Immunol. 2021 Aug 31. pii: S1471-4906(21)00175-7. [Epub ahead of print]

Trust your gut: an early life lesson for T cells.

Jennifer E Cowan.

Zegarra-Ruiz et al. demonstrate that gut microbe-specific T cells are selected within the thymus exclusively during early life in mice. This selection is dependent on CX3CR1+ dendritic cells migrating from the gut carrying bacterially derived antigens into the thymus. This offers new insight into how gut microbiota influence T cell development.

DOI: https://doi.org/10.1016/j.it.2021.08.010

Immunity. 2021 Aug 24. pii: S1074-7613(21)00336-8. [Epub ahead of print]

A subset of Kupffer cells regulates metabolism through the expression of CD36.

Tissue macrophages are immune cells whose phenotypes and functions are dictated by origin and niches. However, tissues are complex environments, and macrophage heterogeneity within the same organ has been overlooked so far. Here, we used high-dimensional approaches to characterize macrophage populations in the murine liver. We identified two distinct populations among embryonically derived Kupffer cells (KCs) sharing a core signature while differentially expressing numerous genes and proteins: a major CD206loESAM- population (KC1) and a minor CD206hiESAM+ population (KC2). KC2 expressed genes involved in metabolic processes, including fatty acid metabolism both in steady-state and in diet-induced obesity and hepatic steatosis. Functional characterization by depletion of KC2 or targeted silencing of the fatty acid transporter Cd36 highlighted a crucial contribution of KC2 in the liver oxidative stress associated with obesity. In summary, our study reveals that KCs are more heterogeneous than anticipated, notably describing a subpopulation wired with metabolic functions.

Keywords: CD206; CD36; Kupffer cells; heterogeneity; high fat diet; liver; macrophages; metabolism; scRNA-seq; single cell

DOI: https://doi.org/10.1016/j.immuni.2021.08.006

J Hepatol. 2021 Aug 25. pii: S0168-8278(21)02006-7. [Epub ahead of print]

Therapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model.

BACKGROUND AND AIMS: Messenger RNA (mRNA)-based therapeutics are rapidly progressing to the clinic and hold tremendous potential for benefiting millions of people worldwide. Therapeutic targeting of injuries that require transient restoration of proteins by mRNA delivery is an attractive aspect, however until recently, it has remained poorly explored. In this study, we examined for the first time, the therapeutic utility of mRNA delivery in liver fibrosis and cirrhosis, which contributes to millions of deaths, annually. Here, we aimed to demonstrate therapeutic efficacy of the human transcription factor hepatocyte nuclear factor alpha (HNF4A) encoding mRNA in chronically injured murine liver leading to fibrosis and cirrhosis.
METHODS: We investigated restoration of hepatocyte functions by HNF4A mRNA transfection in vitro, and analyzed the attenuation of liver fibrosis and cirrhosis in multiple mouse models, by delivering hepatocyte-targeted biodegradable lipid nanoparticles (LNP) encapsulating HNF4A mRNA. To identify potential mechanisms, we performed microarray-based gene expression profiling, single cell RNA sequencing, and chromatin immunoprecipitation. We used primary liver cells and human liver buds for additional functional validation.
RESULTS: Expression of HNF4A encoding mRNA led to restoration of metabolic activity of fibrotic primary murine and human hepatocytes in vitro. Repeated in vivo delivery of HNF4A mRNA encapsulated-LNP induced a robust inhibition of fibrogenesis in four independent mouse models of hepatotoxin- and cholestasis-induced liver fibrosis. Mechanistically, we discovered that paraoxonase 1 is a direct target of HNF4A and it contributes to HNF4A-mediated attenuation of liver fibrosis via modulation of liver macrophages and hepatic stellate cells.
CONCLUSION: Collectively, our findings provide the first direct preclinical evidence of the applicability of HNF4A mRNA therapeutics for the treatment of fibrosis in the liver.
LAY SUMMARY: Liver fibrosis and cirrhosis remain unmet medical needs and contribute to high mortality, worldwide. Herein, we take advantage of a promising, emerging mRNA therapy approach to treat liver fibrosis and cirrhosis. We demonstrate that restoration of a key gene, HNF4A, via mRNA encapsulated in lipid nanoparticles decreased injury in multiple mouse models of fibrosis and cirrhosis. Our study provides the proof-of-concept that mRNA therapy would be a promising strategy for reversing liver fibrosis and cirrhosis.

Keywords: Transcription factors; mRNA therapeutics; protein replacement and cirrhosis

DOI: https://doi.org/10.1016/j.jhep.2021.08.011