scholarly journals RAMP1 in Kupffer cells is a critical regulator in immune-mediated hepatitis

2018 ◽  
Author(s):  
Tomoyoshi Inoue ◽  
Yoshiya Ito ◽  
Nobuyuki Nishizawa ◽  
Koji Eshima ◽  
Ken Kojo ◽  
...  
Keyword(s):  
T Cells ◽  
Liver Injury ◽  
Kupffer Cells ◽  
Immune Cells ◽  
Critical Role ◽  
Dependent Manner ◽  
Immune Mediated ◽  
A Subunit ◽  
Sensory Nervous System ◽  
Deficient Mice

AbstractThe significanceF of the relationship between the nervous and immune systems with respect to disease course is increasingly apparent. Immune cells in the liver and spleen are responsible for the development of acute liver injury, yet the regulatory mechanisms of the interactions remain elusive. Calcitonin gene-related peptide (CGRP), which is released from the sensory nervous system, regulates innate immune activation via receptor activity-modifying protein 1 (RAMP1), a subunit of the CGRP receptor. Here, we show that RAMP1 in Kupffer cells (KCs) plays a critical role in the etiology of immune-mediated hepatitis. RAMP1-deficient mice with concanavalin A (ConA)-mediated hepatitis, characterized by severe liver injury accompanied by infiltration of immune cells and increased secretion of pro-inflammatory cytokines by KCs and splenic T cells, showed poor survival. Removing KCs ameliorated liver damage, while depleting T cells or splenectomy led to partial amelioration. Adoptive transfer of splenic T cells from RAMP1-deficient mice led to a modest increase in liver injury. Co-culture of KCs with splenic T cells led to increased cytokine expression by both cells in a RAMP1-dependent manner. Thus, immune-mediated hepatitis develops via crosstalk between immune cells. RAMP1 in KCs is a key regulator of immune responses.

scholarly journals Mesenchymal stem cells alleviate experimental immune-mediated liver injury via chitinase 3-like protein 1-mediated T cell suppression

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Qiuli Liu ◽  
Xiaoyong Chen ◽  
Chang Liu ◽  
Lijie Pan ◽  
Xinmei Kang ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Liver Injury ◽  
T Cell Activation ◽  
Gene Set Enrichment Analysis ◽  
Human Umbilical Cord ◽  
Con A ◽  
Immune Mediated

AbstractLiver diseases with different pathogenesis share common pathways of immune-mediated injury. Chitinase-3-like protein 1 (CHI3L1) was induced in both acute and chronic liver injuries, and recent studies reported that it possesses an immunosuppressive ability. CHI3L1 was also expressed in mesenchymal stem cells (MSCs), thus we investigates the role of CHI3L1 in MSC-based therapy for immune-mediated liver injury here. We found that CHI3L1 was highly expressed in human umbilical cord MSCs (hUC-MSCs). Downregulating CHI3L1 mitigated the ability of hUC-MSCs to inhibit T cell activation, proliferation and inflammatory cytokine secretion in vitro. Using Concanavalin A (Con A)-induced liver injury mouse model, we found that silencing CHI3L1 significantly abrogated the hUC-MSCs-mediated alleviation of liver injury, accompanying by weakened suppressive effects on infiltration and activation of hepatic T cells, and secretion of pro-inflammatory cytokines. In addition, recombinant CHI3L1 (rCHI3L1) administration inhibited the proliferation and function of activated T cells, and alleviated the Con A-induced liver injury in mice. Mechanistically, gene set enrichment analysis showed that JAK/STAT signalling pathway was one of the most significantly enriched gene pathways in T cells co-cultured with hUC-MSCs with CHI3L1 knockdown, and further study revealed that CHI3L1 secreted by hUC-MSCs inhibited the STAT1/3 signalling in T cells by upregulating peroxisome proliferator-activated receptor δ (PPARδ). Collectively, our data showed that CHI3L1 was a novel MSC-secreted immunosuppressive factor and provided new insights into therapeutic treatment of immune-mediated liver injury.

scholarly journals Eomes Impedes Durable Response to Tumor Immunotherapy by Inhibiting Stemness, Tissue Residency, and Promoting the Dysfunctional State of Intratumoral CD8+ T Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Runzi Sun ◽  
Yixian Wu ◽  
Huijun Zhou ◽  
Yanshi Wu ◽  
Zhongzhou Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Critical Role ◽  
Cell Subset ◽  
Tumor Immunotherapy ◽  
Genetic Circuit ◽  
Durable Response ◽  
T Cell Immune Responses ◽  
Deficient Mice

Sustaining efficacious T cell-mediated antitumor immune responses in the tumor tissues is the key to the success of cancer immunotherapy. Current strategies leverage altering the signals T cells sense in the tumor microenvironment (TME). Checkpoint inhibitor-based approaches block inhibitory signals such as PD-1 whereas cytokine-based therapies increase the level of immune-stimulatory cytokines such as IL-2. Besides extrinsic signals, the genetic circuit within T cells also participates in determining the nature and trajectory of antitumor immune responses. Here, we showed that efficacy of the IL33-based tumor immunotherapy was greatly enhanced in mice with T cell-specific Eomes deficiency. Mechanistically, we demonstrated that Eomes deficient mice had diminished proportions of exhausted/dysfunctional CD8+ T cells but increased percentages of tissue resident and stem-like CD8+ T cells in the TME. In addition, the IFNγ+TCF1+ CD8+ T cell subset was markedly increased in the Eomes deficient mice. We further demonstrated that Eomes bound directly to the transcription regulatory regions of exhaustion and tissue residency genes. In contrast to its role in inhibiting T cell immune responses at the tumor site, Eomes promoted generation of central memory T cells in the peripheral lymphoid system and memory recall responses against tumor growth at a distal tissue site. Finally, we showed that Eomes deficiency in T cells also resulted in increased efficacy of PD-1-blockade tumor immunotherapy. In all, our study indicates that Eomes plays a critical role in restricting prolonged T cell-mediated antitumor immune responses in the TME whereas promoting adaptive immunity in peripheral lymphoid organs.

scholarly journals Prognostic significance of natural killer cell-associated markers in gastric cancer: quantitative analysis using multiplex immunohistochemistry

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hee Young Na ◽  
Yujun Park ◽  
Soo Kyung Nam ◽  
Jiwon Koh ◽  
Yoonjin Kwak ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
B Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Prognostic Significance

Abstract Background Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC). Methods We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells. Results Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival. Conclusions Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC.

scholarly journals The role of the Th1 transcription factor T-bet in a mouse model of immune-mediated bone-marrow failure

Blood ◽  
2010 ◽  
Vol 115 (3) ◽  
pp. 541-548 ◽  
Author(s):  
Yong Tang ◽  
Marie J. Desierto ◽  
Jichun Chen ◽  
Neal S. Young
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Transcription Factor ◽  
Transforming Growth Factor ◽  
Bone Marrow Failure ◽  
Critical Role ◽  
Interferon Γ ◽  
Interleukin 17 ◽  
Immune Mediated

Abstract The transcription factor T-bet is a key regulator of type 1 immune responses. We examined the role of T-bet in an animal model of immune-mediated bone marrow (BM) failure using mice carrying a germline T-bet gene deletion (T-bet−/−). In comparison with normal C57BL6 (B6) control mice, T-bet−/− mice had normal cellular composition in lymphohematopoietic tissues, but T-bet−/− lymphocytes were functionally defective. Infusion of 5 × 106 T-bet−/− lymph node (LN) cells into sublethally irradiated, major histocompatibility complex–mismatched CByB6F1 (F1) recipients failed to induce the severe marrow hypoplasia and fatal pancytopenia that is produced by injection of similar numbers of B6 LN cells. Increasing T-bet−/− LN-cell dose to 10 to 23 × 106 per recipient led to only mild hematopoietic deficiency. Recipients of T-bet−/− LN cells had no expansion in T cells or interferon-γ–producing T cells but showed a significant increase in Lin−Sca1+CD117+CD34− BM cells. Plasma transforming growth factor-β and interleukin-17 concentrations were increased in T-bet−/− LN-cell recipients, possibly a compensatory up-regulation of the Th17 immune response. Continuous infusion of interferon-γ resulted in hematopoietic suppression but did not cause T-bet−/− LN-cell expansion or BM destruction. Our data provided fresh evidence demonstrating a critical role of T-bet in immune-mediated BM failure.

Polycation Coated Polymeric Particles as Vehicles of RNA Delivery Into Immune Cells

2010 ◽  
Author(s):  
Ying Zheng ◽  
Wilson S. Meng
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Messenger Rna ◽  
Flow Cytometric Analysis ◽  
Confocal Imaging ◽  
Dependent Manner ◽  
Carrier System ◽  
Foxp3 Mrna ◽  
Rna Molecules ◽  
Polymeric Particles

The purpose of this work is to develop a carrier system for delivering RNA molecules aimed to downregulate specific functions in T cells. In many forms of cancer, T cells that express the protein Forkhead Box P3 (Foxp3) are associated with cancer progression. These cells can be identified by CD4 and CD25, molecules express on the cell surface. Studies have shown that downregulation of Foxp3 can increase the ability of other immune cells to destroy tumors. A class of RNA molecules, commonly referred to as “siRNA”, bind to and degrade specific messenger RNA (mRNA) in a sequence-dependent manner such that expression of the encoded protein is terminated. Because mRNA molecules are located inside cells, a carrier system is required to facilitate the uptake of siRNA, which does not passively diffuse through the plasma membrane. To this end, nanosized polymeric particles coated with the polycation, ornithinex10-histidinex6 (or O10H6) were used to adsorb siRNA that bind to the mRNA encoding Foxp3. The RNA-loaded particles are spherical and uniform in size (normally distributed, polydispersity index = 0.072). Loading of RNA to the particles was confirmed using gel electrophoresis. RNA complexed with the particles are protected from serum destabilization: 83.1% of RNA were recovered compared to 36.1% in RNA that were not associated with the particles. Association with the particles increased the uptake of the RNA in mouse T cells from 3.2±0.2% (free RNA) to 20.1±3.9%. Specifically, uptake of the RNA in T cells that express CD4 increased from 2.7±0.2% to 27.1±1.3% when particles were employed. These differences are statistically significant in three experiments conducted (p < 0.01). Internalization of the RNA into T cells was confirmed using confocal imaging. Flow cytometric analysis showed that the particle-complexed RNA reduced the percentage of T cells that express both CD4 and CD25 in mice carrying tumors from 24.0% when free RNA molecules were used to 13.5%. In these cells, the level of Foxp3 mRNA was reduced by 30%. In conclusion, the particles facilitate the uptake of siRNA molecules into a population of T cells that is known to promote cancer growth.

Activation of human and mouse Kupffer cells by lipopolysaccharide is mediated by CD14

2002 ◽  
Vol 283 (3) ◽  
pp. G640-G645 ◽  
Author(s):  
Grace L. Su ◽  
Sanna M. Goyert ◽  
Ming-Hui Fan ◽  
Alireza Aminlari ◽  
Ke Qin Gong ◽  
...  
Keyword(s):  
Kupffer Cell ◽  
Kupffer Cells ◽  
Knockout Mice ◽  
Cell Activation ◽  
Critical Role ◽  
Dependent Manner ◽  
Liver Macrophage ◽  
Tnf Α ◽  
Presence And Absence ◽  
Lps Activation

Upregulation of CD14 in Kupffer cells has been implicated in the pathogenesis of several forms of liver injury, including alcoholic liver disease. However, it remains unclear whether CD14 mediates lipopolysaccharide (LPS) signaling in this specialized liver macrophage population. In this series of experiments, we determined the role of CD14 in LPS activation of Kupffer cells by using several complementary approaches. First, we isolated Kupffer cells from human livers and studied the effects of anti-CD14 antibodies on LPS activation of these cells. Kupffer cells were incubated with increasing concentrations of LPS in the presence and absence of recombinant human LPS binding protein (LBP). With increasing concentrations of LPS, human Kupffer cell tumor necrosis factor-α (TNF-α) production (a marker for Kupffer cell activation) increased in a dose-dependent manner in the presence and absence of LBP. In the presence of anti-human CD14 antibodies, the production of TNF-α was significantly diminished. Second, we compared LPS activation of Kupffer cells isolated from wild-type and CD14 knockout mice. Kupffer cells from CD14 knockout mice produced significantly less TNF-α in response to the same amount of LPS. Together, these data strongly support a critical role for CD14 in Kupffer cell responses to LPS.

scholarly journals Natural killer T cells play a necessary role in modulating of immune-mediated liver injury by gut microbiota

2014 ◽  
Vol 4 (1) ◽  
Author(s):  
Jianing Chen ◽  
Yingfeng Wei ◽  
Jianqin He ◽  
Guangying Cui ◽  
Yunan Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
Liver Injury ◽  
Gut Microbiota ◽  
Natural Killer ◽  
Natural Killer T Cells ◽  
Immune Mediated ◽  
Killer T Cells ◽  
Natural Killer T

scholarly journals IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice

Hepatology ◽  
2007 ◽  
Vol 45 (2) ◽  
pp. 475-485 ◽  
Author(s):  
Annette Erhardt ◽  
Markus Biburger ◽  
Thomas Papadopoulos ◽  
Gisa Tiegs
Keyword(s):  
T Cells ◽  
Liver Injury ◽  
Regulatory T Cells ◽  
Kupffer Cells ◽  
Concanavalin A

scholarly journals Nuclear Factor of Activated T Cells (NFAT)-dependent Transactivation Regulated by the Coactivators p300/CREB-binding Protein (CBP)

1998 ◽  
Vol 187 (12) ◽  
pp. 2031-2036 ◽  
Author(s):  
Carmen García-Rodríguez ◽  
Anjana Rao
Keyword(s):  
T Cells ◽  
Binding Protein ◽  
Critical Role ◽  
Regulation Of Transcription ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Transactivation Domain ◽  
Creb Binding Protein ◽  
Activated T Cells ◽  
Viral Oncoprotein

p300 and cAMP response element–binding protein (CREB)–binding protein (CBP) are members of a family of coactivators involved in the regulation of transcription and chromatin. We show that transcription factors of the nuclear factor of activated T cells (NFAT) family bind p300/CBP and recruit histone acetyltransferase activity from T cell nuclear extracts. The NH2-terminal transactivation domain of NFAT1 and the phospho-CREB- and E1A-binding sites of p300/CBP are involved in the interaction. The viral oncoprotein E1A inhibits NFAT-dependent transactivation in a p300-dependent manner. Recruitment of the coactivators p300/CBP by the transactivation domains of NFAT proteins is likely to play a critical role in NFAT-dependent gene expression during the immune response.

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