Mechanism of inert inflammation in an immune checkpoint blockade-resistant tumor subtype bearing transcription elongation defects.

The clinical response to immune checkpoint blockade (ICB) correlates with tumor-infiltrating cytolytic T lymphocytes (CTLs) prior to treatment. However, many of these inflamed tumors resist ICB through unknown mechanisms. We show that tumors with transcription elongation deficiencies (TE), which we previously reported as being resistant to ICB in mouse models and the clinic, have high baseline CTLs.

Targeting of Cdc42 GTPase in regulatory T cells unleashes antitumor T-cell immunity.

Background: Cancer immunotherapy has taken center stage in cancer treatment. However, the current immunotherapies only benefit a small proportion of patients with cancer, necessitating better understanding of the mechanisms of tumor immune evasion and improved cancer immunotherapy strategies. Regulatory T (Treg) cells play an important role in maintaining immune tolerance through inhibiting effector T-cell function.

Chrysin sensitizes osteosarcoma cells against TRAIL-induced apoptosis.

Identifying novel curative and preventive approaches that can specifically target the osteosarcoma cells (OS) without affecting the normal cells is appreciable. The aim of this study is to investigate the combined effect of chrysin as an apigenin analog with high therapeutic potential and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the treatment of Saos-2 and MG-63 cells. Cell viability were determined using MTT method.

Graded RhoA GTPase Expression in Treg Cells Distinguishes Tumor Immunity From Autoimmunity.

RhoA of the Rho GTPase family is prenylated at its C-terminus. Prenylation of RhoA has been shown to control T helper 17 (Th17) cell-mediated colitis. By characterizing T cell-specific RhoA conditional knockout mice, we have recently shown that RhoA is required for Th2 and Th17 cell differentiation and Th2/Th17 cell-mediated allergic airway inflammation.

Inhibition of Rho-Kinase Downregulates Th17 Cells and Ameliorates Hepatic Fibrosis by Infection.

Background: Schistosomiasis is an immunopathogenic disease in which Th17 cells play vital roles. Hepatic granuloma formation and subsequent fibrosis are its main pathologic manifestations and the leading causes of hepatic cirrhosis, and effective therapeutic interventions are lacking. In this study, we explored the effects of fasudil, a selective RhoA-Rho-associated kinase (ROCK) inhibitor, on Th17 cells and the pathogenesis of schistosomiasis.

[Roles of transforming growth factor - β1 and heat shock protein 47 in progression of -induced hepatic fibrosis].

Objective: To investigate the dynamic expression of transforming growth factor-β1 (TGF-β1) and heat shock protein 47 (HSP47) and explore their roles in the progression of hepatic fibrosis induced by infection.

Methods: Fifty female mice of the ICR strain were randomly divided into the infection group and the normal control group, of 25 mice in each group. Each mouse in the infection group was infected with 20 ± 1 cercariae of via the abdominal skin, while uninfected animals served as normal control.

Ablation of RhoA impairs Th17 cell differentiation and alleviates house dust mite-triggered allergic airway inflammation.

Asthma is a heterogeneous chronic airway inflammation in which Th2 and Th17 cells are key players in its pathogenesis. We have reported that RhoA of Rho GTPases orchestrated glycolysis for Th2 cell differentiation and allergic airway inflammation by the use of a conditional RhoA-deficient mouse line. However, the role of RhoA in Th17 cells remains to be elucidated.

Antinociceptive effects of Ginsenoside Rb1 in a rat model of cancer-induced bone pain.

Ginsenoside Rb1 (GRb1) is a major ingredient of ginseng, a traditional medicine that has been used for thousands of years. Previous studies have reported that GRb1 had anti-inflammatory, antioxidant and neuroprotective effects. The current study aimed to evaluate the antinociceptive effects of GRb1 in a rat model of cancer-induced bone pain (CIBP) established by intratibial injection of Walker 256 cells.

[Advances in the regulatory roles of exosomes on pathological process of schistosomiasis hepatic fibrosis].

Exosomes are a group of membraneous vesicles generated and released by multi-vesicular bodies or cell membranes in a variety of cell types. Acting as important messages between cells, they participate in almost every physiological and pathological process of living organisms. Exosomes contain specific proteins, mRNA, miRNAs, etc.

Rational targeting Cdc42 restrains Th2 cell differentiation and prevents allergic airway inflammation.

Background: Asthma is an allergic airway inflammation-driven disease that affects more than 300 million people world-wide. Targeted therapies for asthma are largely lacking. Although asthma symptoms can be prevented from worsening, asthma development cannot be prevented.

[Role of Rho GTPases in the immune regulation of infection and inflammation].

The Rho subfamily of GTPase belongs to the Ras superfamily of small GTP binding protein, it is a nucleotide dependent protein, which plays a "molecular switch" function in the signal transduction process and control of numerous signaling pathways. Rho protein has many biological effects on cytoskeleton or target proteins as a signal converter in signal transduction, such as the regulation of membrane transport function, cell migration, cell adhesion, and cell proliferation. It also plays a very important role in the infection and immune inflammation of the body.

[Immunomodulatory effects of Treg and Th17 cells in parasitic infections and hygiene hypothesis].

The parasitic infection is still a severe public health problem in developing countries, which threatens people's health and social development. With the advances of molecular biology and immunology, more and more insights have been reached on the immunity and immunopathogenesis to parasitic infections. CD4 T cells play a central role in the host's immunosurveillance and immunoregulation.

Reciprocal Regulation of Glycolysis-Driven Th17 Pathogenicity and Regulatory T Cell Stability by Cdc42.

A balance between Th17 cells and regulatory T cells (Tregs) is important for host immunity and immune tolerance. The underlying molecular mechanisms remain poorly understood. Here we have identified Cdc42 as a central regulator of Th17/Treg balance.

PKCλ/ι regulates Th17 differentiation and house dust mite-induced allergic airway inflammation.

Asthma is a chronic airway inflammation in which Th2 and Th17 cells play critical roles in its pathogenesis. We have reported that atypical protein kinase (PKC) λ/ι is a new regulator for Th2 differentiation and function. However, the role of PKCλ/ι for Th17 cells remains elusive.

Correction: Schistosoma japonicum infection downregulates house dust mite-induced allergic airway inflammation in mice.

[This corrects the article DOI: 10.1371/journal.pone.

mTOR has a developmental stage-specific role in mitochondrial fitness independent of conventional mTORC1 and mTORC2 and the kinase activity.

The mammalian target of rapamycin (mTOR), present in mTOR complex 1 (mTORC1) and mTORC2, is a serine/threonine kinase that integrates nutrients, growth factors, and cellular energy status to control protein synthesis, cell growth, survival and metabolism. However, it remains elusive whether mTOR plays a developmental stage-specific role in tissue development and whether mTOR can function independent of its complexes and kinase activity. In this study, by inducible genetic manipulation approach, we investigated the role of mTOR and its dependence on mTOR complexes and kinase activity in mitochondrial fitness of early, progenitor stage (lineage-negative; Lin-) versus later, lineage-committed stage (lineage-positive; Lin+) of hematopoietic cells.

Schistosoma japonicum infection downregulates house dust mite-induced allergic airway inflammation in mice.

The "hygiene hypothesis" is a theory try to explain the dramatic increases in the prevalence of autoimmune and allergic diseases over the past two to three decades in developed countries. According to this theory, reduced exposure to parasites and microorganisms in childhood is the main cause for the increased incidences of both T helper 1 (Th1)-mediated autoimmunity and Th2-mediated allergy. In this study, we investigated the impact of Schistosoma japonicum infection on the allergic airway inflammation induced by repeated intracheal inoculations of house dust mites (HDM), which is a Th17 and neutrophils dominant murine asthma model, mimicking severe asthma.

Effects of Invariant NKT Cells on Parasite Infections and Hygiene Hypothesis.

Invariant natural killer T (iNKT) cells are unique subset of innate-like T cells recognizing glycolipids. iNKT cells can rapidly produce copious amounts of cytokines upon antigen stimulation and exert potent immunomodulatory activities for a wide variety of immune responses and diseases. We have revealed the regulatory effect of iNKT cells on autoimmunity with a serial of publications.

[Dynamics of CD4⁺ T cell subsets and their roles in schistosome infections: a review].

Schistosomiasis is a chronic helminthic disease that affects about two hundred millions of people in the world. The pathogenesis of schistosome infection is primarily due to hepatic and intestinal granuloma formation around deposited eggs and subsequent fibrosis. It is known that CD4⁺ T cell subsets play critical roles in the host immunity and immunopathogenesis to schistosome infections, in which T helper 1 (Th1) and Th2 cells are major effector T cell subsets, whereas T regulatory (Treg) cells exert immunosuppressive roles in general.

RhoA orchestrates glycolysis for TH2 cell differentiation and allergic airway inflammation.

Background: Mitochondrial metabolism is known to be important for T-cell activation. However, its involvement in effector T-cell differentiation has just begun to gain attention. Importantly, how metabolic pathways are integrated with T-cell activation and effector cell differentiation and function remains largely unknown.

Gene targeting RhoA reveals its essential role in coordinating mitochondrial function and thymocyte development.

Thymocyte development is regulated by complex signaling pathways. How these signaling cascades are coordinated remains elusive. RhoA of the Rho family small GTPases plays an important role in actin cytoskeleton organization, cell adhesion, migration, proliferation, and survival.

Mouse gene targeting reveals an essential role of mTOR in hematopoietic stem cell engraftment and hematopoiesis.

mTOR integrates signals from nutrients and growth factors to control protein synthesis, cell growth, and survival. Although mTOR has been established as a therapeutic target in hematologic malignancies, its physiological role in regulating hematopoiesis remains unclear. Here we show that conditional gene targeting of mTOR causes bone marrow failure and defects in multi-lineage hematopoiesis including myelopoiesis, erythropoiesis, thrombopoiesis, and lymphopoiesis.

Germline deletion of β2 microglobulin or CD1d reduces anti-phospholipid antibody, but increases autoantibodies against non-phospholipid antigens in the NZB/W F1 model of lupus.

Introduction: β2-microglobulin (β2m) is required for the surface expression of MHC class I and class I-like proteins such as CD1d, Qa1 and neonatal Fc receptor (FcRn), all of which may impact the development of autoimmunity. Since CD1d is known to bind and present phospholipid antigens to T cells, we asked if the deficiency of β2m or CD1d will impact the development of anti-phospholipid antibodies as compared to other aspects of lupus autoimmunity.

Methods: We introgressed the β2m-null genotype onto the NZB and NZW backgrounds for 12 to 14 generations to generate genetically lupus-susceptible (NZB/NZW)F1 (BWF1) mice that are β2m-deficient (β2m°).

Homeostatic regulation of marginal zone B cells by invariant natural killer T cells.

Marginal zone B cells (MZB) mount a rapid antibody response, potently activate naïve T cells, and are enriched in autoreactive B cells. MZBs express high levels of CD1d, the restriction element for invariant natural killer T cells (iNKT). Here, we examined the effect of iNKT cells on MZB cell activation and numbers in vitro and in vivo in normal and autoimmune mice.

Brief treatment with iNKT cell ligand α-galactosylceramide confers a long-term protection against lupus.

CD1d presents glycolipid antigens such as α-galactosylceramide (αGalCer) to invariant natural killer T cells (iNKT). We have reported that activated iNKTs inhibit IL-10-producing autoreactive B cells, while promoting or leaving intact the normal B cell responses, making iNKT modulation an attractive therapeutic modality. Here, we report that a brief treatment of young lupus-prone (NZB/NZW)F1 (BWF1) mice with two injections of αGalCer conferred a long-term protection against lupus.