In drug-induced, immune-mediated hepatitis, interleukin-33 reduces hepatitis and improves survival independently and as a consequence of FoxP3+ T-cell activity

Cottagiri, Merylin; Nyandjo, Maeva; Stephens, Matthew; Mantilla, Joel J.; Saito, Hirohisa; Mackay, Ian R.; Rose, Noel R.; Njoku, Dolores B.

doi:10.1038/s41423-018-0087-y

Cited by 13 publications

(10 citation statements)

References 33 publications

(58 reference statements)

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“…Our recent studies support the notion that IL-33, is protective in male mice with NASH and possibly in the associated cardiomyopathy [20]. Our prior investigations also support anti-inflammatory roles for IL-33 in drug-induced hepatitis via FoxP3þ Tregs and IL-10 [40]. However, IL-33 activates numerous signaling pathways by binding to ST2L, expressed on various cells [41].…”

Section: A Proposed Mechanism Of Crosstalk Between the Hepatic And Ca...supporting

confidence: 84%

Mechanisms of nonalcoholic steatohepatitis-associated cardiomyopathy: key roles for liver–heart crosstalk

Njoku¹,

Schilling²,

Finck

2022

Current Opinion in Lipidology

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Purpose of reviewNonalcoholic steatohepatitis (NASH) is a multisystem disease that affects not only the liver but also heart, pancreas, and kidney. We currently lack a comprehensive understanding of mechanisms responsible for the development of NASH-associated cardiomyopathy or the influence of sex on pathophysiology. There is a critical need to address these gaps in knowledge in order to accelerate translation of knowledge into clinical practice. Recent findingsNASH and cardiovascular disease share common risk factors such as chronic inflammation, hyperlipidemia, and insulin resistance. Early cardiac dysfunction in NASH that is independent of obesity or other cardiometabolic risk factors suggests roles for liver--heart crosstalk in disease pathogenesis. Inflammation is a driving force in the pathogenesis of NASH, and it is likely that 'spill over' of NASH inflammation contributes to the development of cardiomyopathy. However, molecular and cellular mechanisms that mediate NASH-associated cardiomyopathy remain unclear because of inherent limitations of experimental models. Even so, recent studies implicate inflammatory, metabolic, and physiologic mechanisms that enhance our understanding of NASH-associated cardiomyopathy and the role of liver-heart crosstalk. SummaryAn innovative, detailed, and mechanistic understanding of NASH-associated cardiomyopathy is relevant to public health and will be fundamental for the comprehensive care of these patients.

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Section: A Proposed Mechanism Of Crosstalk Between the Hepatic And Ca...supporting

confidence: 84%

Mechanisms of nonalcoholic steatohepatitis-associated cardiomyopathy: key roles for liver–heart crosstalk

Njoku¹,

Schilling²,

Finck

2022

Current Opinion in Lipidology

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“…The Tregs negatively regulate effective T cell immune responses via the production of immunosuppressive cytokines (including IL-10 and TGF-β) during chronic infection and are considered to be a potential target for the treatment of patients with CHB (7). Through upregulated Tregs, IL-33 exerts a negative effect on CD4 + T cell proliferation and alleviates hepatitis (76). Similarly, it was found that Tregs orchestrate CD8 + T cell exhaustion by engaging the PD-1 inhibitory pathway during LCMV infection (77).…”

Section: The Adaptive Immune Tolerance Mechanismsmentioning

confidence: 99%

Liver-Mediated Adaptive Immune Tolerance

2019

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The liver is an immunologically tolerant organ that is uniquely equipped to limit hypersensitivity to food-derived antigens and bacterial products through the portal vein and can feasibly accept liver allografts. The adaptive immune response is a major branch of the immune system that induces organ/tissue-localized and systematic responses against pathogens and tumors while promoting self-tolerance. Persistent infection of the liver with a virus or other pathogen typically results in tolerance, which is a key feature of the liver. The liver's immunosuppressive microenvironment means that hepatic adaptive immune cells become readily tolerogenic, promoting the death of effector cells and the “education” of regulatory cells. The above mechanisms may result in the clonal deletion, exhaustion, or inhibition of peripheral T cells, which are key players in the adaptive immune response. These tolerance mechanisms are believed to be responsible for almost all liver diseases. However, optimal protective adaptive immune responses may be achieved through checkpoint immunotherapy and the modulation of hepatic innate immune cells in the host. In this review, we focus on the mechanisms involved in hepatic adaptive immune tolerance, the liver diseases caused thereby, and the therapeutic strategies needed to overcome this tolerance.

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“…IL4 is a well-known Th2-promoting cytokine. 44,45 Paradoxically, IL4 from iNKT cells promoted STAT6 phosphorylation and IL12 production in DCs and enhanced iNKT cell-mediated Th1 responses (Fig. 2).…”

Section: Discussionmentioning

confidence: 93%

Spatial distribution of IL4 controls iNKT cell-DC crosstalk in tumors

et al. 2019

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The spatiotemporal distribution of cytokines orchestrates immune responses in vivo, yet the underlying mechanisms remain to be explored. We showed here that the spatial distribution of interleukin-4 (IL4) in invariant natural killer T (iNKT) cells regulated crosstalk between iNKT cells and dendritic cells (DCs) and controlled iNKT cell-mediated T-helper type 1 (Th1) responses. The persistent polarization of IL4 induced by strong lipid antigens, that is, α-galactosylceramide (αGC), caused IL4 accumulation at the immunological synapse (IS), which promoted the activation of the IL4R-STAT6 (signal transducer and activator of transcription 6) pathway and production of IL12 in DCs, which enhanced interferon-γ (IFNγ) production in iNKT cells. Conversely, the nonpolarized secretion of IL4 induced by Th2 lipid antigens with a short or unsaturated chain was incapable of enhancing this iNKT cell-DC crosstalk and thus shifted the immune response to a Th2-type response. The nonpolarized secretion of IL4 in response to Th2 lipid antigens was caused by the degradation of Cdc42 in iNKT cells. Moreover, reduced Cdc42 expression was observed in tumorinfiltrating iNKT cells, which impaired IL4 polarization and disturbed iNKT cell-DC crosstalk in tumors.

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In drug-induced, immune-mediated hepatitis, interleukin-33 reduces hepatitis and improves survival independently and as a consequence of FoxP3+ T-cell activity

Cited by 13 publications

References 33 publications

Mechanisms of nonalcoholic steatohepatitis-associated cardiomyopathy: key roles for liver–heart crosstalk

Mechanisms of nonalcoholic steatohepatitis-associated cardiomyopathy: key roles for liver–heart crosstalk

Liver-Mediated Adaptive Immune Tolerance

Spatial distribution of IL4 controls iNKT cell-DC crosstalk in tumors

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