Differential Role of Cathepsins S and B In Hepatic APC-Mediated NKT Cell Activation and Cytokine Secretion

Pulido, Álvaro de Mingo; Gregorio, Estefanía de; Chandra, Shilpi; Colell, Anna; Morales, Albert; Kronenberg, Mitchell; Marı́, Montserrat

doi:10.3389/fimmu.2018.00391

Cited by 15 publications

(12 citation statements)

References 66 publications

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“…Continuing, Ctsb is deemed relevant in the lysosomal processing of external antigens for their further presentation by antigen presenting cells. Its inhibition has been recently associated with the activation of APC-mediated anti-inflammatory immunity in hepatic pathology (54). Here we also reported the negative regulation of two subunits of the proteasome: the β8 subunit of the immunoproteasome (Psmb8) and the canonical β4 from the 20S core complex (Psmb4) suggesting a possible regulatory process related to proteasome-mediated protein degradation.…”

Section: Discussionmentioning

confidence: 99%

The Schistosomiasis SpleenOME: Unveiling the Proteomic Landscape of Splenomegaly Using Label-Free Mass Spectrometry

et al. 2019

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Schistosomiasis is a neglected parasitic disease that affects millions of people worldwide and is caused by helminth parasites from the genus Schistosoma. When caused by S. mansoni, it is associated with the development of a hepatosplenic disease caused by an intense immune response to the important antigenic contribution of adult worms and to the presence of eggs trapped in liver tissue. Although the importance of the spleen for the establishment of immune pathology is widely accepted, it has received little attention in terms of the molecular mechanisms operating in response to the infection. Here, we interrogated the spleen proteome using a label-free shotgun approach for the potential discovery of molecular mechanisms associated to the peak of the acute phase of inflammation and the development of splenomegaly in the murine model. Over fifteen hundred proteins were identified in both infected and control individuals and 325 of those proteins were differentially expressed. Two hundred and forty-two proteins were found upregulated in infected individuals while 83 were downregulated. Functional enrichment analyses for differentially expressed proteins showed that most of them were categorized within pathways of innate and adaptive immunity, DNA replication, vesicle transport and catabolic metabolism. There was an important contribution of granulocyte proteins and antigen processing and presentation pathways were augmented, with the increased expression of MHC class II molecules but the negative regulation of cysteine and serine proteases. Several proteins related to RNA processing were upregulated, including splicing factors. We also found indications of metabolic reprogramming in spleen cells with downregulation of proteins related to mitochondrial metabolism. Ex-vivo imunophenotyping of spleen cells allowed us to attribute the higher abundance of MHC II detected by mass spectrometry to increased number of macrophages (F4/80+/MHC II+ cells) in the infected condition. We believe these findings add novel insights for the understanding of the immune mechanisms associated with the establishment of schistosomiasis and the processes of immune modulation implied in the host-parasite interactions.

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Section: Discussionmentioning

confidence: 99%

The Schistosomiasis SpleenOME: Unveiling the Proteomic Landscape of Splenomegaly Using Label-Free Mass Spectrometry

et al. 2019

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“…Triton lysis buffer was used for protein extraction of both LX-2 cells and liver tissue samples. Nuclear extracts from RAW264.7 cells were isolated as previously described [21]. Proteins were separated by molecular weight by electrophoresis using a sodium dodecylsulfate polyacrylamide gel and transferred to a nitrocellulose membrane.…”

Section: Methodsmentioning

confidence: 99%

A Nutraceutical Rich in Docosahexaenoic Acid Improves Portal Hypertension in a Preclinical Model of Advanced Chronic Liver Disease

Boyer‐Díaz¹,

Domingo

Gregorio

et al. 2019

Nutrients

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Inflammation and oxidative stress play a key role in the pathophysiology of advanced chronic liver disease (ACLD) and portal hypertension (PH). Considering the current lack of effective treatments, we evaluated an anti-inflammatory and antioxidant nutraceutical rich in docosahexaenoic acid (DHA) as a possible therapy for ACLD. We investigated the effects of two-week DHA supplementation (500 mg/kg) on hepatic fatty acids, PH, oxidative stress, inflammation, and hepatic stellate cell (HSC) phenotype in rats with ACLD. Additionally, the effects of DHA were evaluated in murine macrophages and human HSC. In contrast to vehicle-treated animals, cirrhotic rats receiving DHA reestablished a healthy hepatic fatty acid profile, which was associated with an improvement in PH. The mechanisms underlying this hemodynamic improvement included a reduction in oxidative stress and inflammation, as well as a marked HSC deactivation, confirmed in human HSC. Experiments with cultured macrophages showed that treatment with DHA protects against pro-inflammatory insults. The present preclinical study demonstrates that a nutraceutical rich in DHA significantly improves PH in chronic liver disease mainly by suppressing inflammation and oxidative stress-driven HSC activation, encouraging its evaluation as a new treatment for PH and cirrhosis.

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“…Inflammation and wound healing are interconnected processes where inflammatory signals compel immune cells towards the site of injury [ 15 ]. Consequently, repair and regeneration of injured tissue occur via apoptotic and regenerative mechanisms [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Fagonia indica Repairs Hepatic Damage through Expression Regulation of Toll-Like Receptors in a Liver Injury Model

Azam

Sheikh

Ali

et al. 2018

Journal of Immunology Research

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Fagonia indica is a traditionally used phytomedicine to cure hepatic ailments. However, efficient validation of its hepatoprotective effect and molecular mechanisms involved are not yet well established. Therefore, the present study was designed to evaluate the hepatoprotective activity of Fagonia indica and to understand the molecular mechanisms involved in the reversal of hepatic injury. The liver injury mouse model was established by thioacetamide followed by oral administration of plant extract. Serum biochemical and histological analyses were performed to assess the level of hepatic injury. Expression analysis of proinflammatory, hepatic, and immune regulatory genes was performed with RT-PCR. Results of serological and histological analyses described the restoration of normal liver function and architecture in mice treated with plant extract. In addition, altered expression of proinflammatory (IL-1β, IL-6, TNF-α, and TGF-β) and hepatic (krt-18 and albumin) markers further strengthens the liver injury reversal effects of Fagonia indica. Furthermore, a significant expression regulation of innate immunity components such as toll-like receptors 4 and 9 and MyD-88 was observed suggesting an immune regulatory role of the plant in curing liver injury. In conclusion, the current study not only proposes Fagonia indica, a strong hepatoprotective candidate, but also recommends an immune regulatory toll-like receptor pathway as an important therapeutic target in liver diseases.

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Differential Role of Cathepsins S and B In Hepatic APC-Mediated NKT Cell Activation and Cytokine Secretion

Cited by 15 publications

References 66 publications

The Schistosomiasis SpleenOME: Unveiling the Proteomic Landscape of Splenomegaly Using Label-Free Mass Spectrometry

The Schistosomiasis SpleenOME: Unveiling the Proteomic Landscape of Splenomegaly Using Label-Free Mass Spectrometry

A Nutraceutical Rich in Docosahexaenoic Acid Improves Portal Hypertension in a Preclinical Model of Advanced Chronic Liver Disease

Fagonia indica Repairs Hepatic Damage through Expression Regulation of Toll-Like Receptors in a Liver Injury Model

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