Inflammatory Modulation Effect of Glycopeptide fromGanoderma capense(Lloyd) Teng

Megakaryoblastic leukemia 1 (MKL1) deficiency is one of the most recently discovered primary immunodeficiencies (PIDs) caused by cytoskeletal abnormalities. These immunological “actinopathies” primarily affect hematopoietic cells, resulting in defects in both the innate immune system (phagocyte defects) and adaptive immune system (T-cell and B-cell defects). MKL1 is a transcriptional coactivator that operates together with serum response factor (SRF) to regulate gene transcription. The MKL/SRF pathway has been originally described to have important functions in actin regulation in cells. Recent results indicate that MKL1 also has very important roles in immune cells, and that MKL1 deficiency results in an immunodeficiency affecting the migration and function of primarily myeloid cells such as neutrophils. Interestingly, several actinopathies are caused by mutations in genes which are recognized MKL(1/2)-dependent SRF-target genes, namely ACTB, WIPF1, WDR1, and MSN. Here we summarize these and related (ARPC1B) actinopathies and their effects on immune cell function, especially focusing on their effects on leukocyte adhesion and migration. Furthermore, we summarize recent therapeutic efforts targeting the MKL/SRF pathway in disease.

Download Full-text

T-cell dysfunction in chronic lymphocytic leukemia from an epigenetic perspective

Haematologica ◽

10.3324/haematol.2020.267914 ◽

2021 ◽

Author(s):

Fleur S. Peters ◽

Jonathan C. Strefford ◽

Eric Eldering ◽

Arnon P. Kater

Keyword(s):

T Cell ◽

Chronic Lymphocytic Leukemia ◽

Molecular Mechanisms ◽

Cell Function ◽

Immune Cell ◽

Lymphocytic Leukemia ◽

T Cell Therapy ◽

High Expectations ◽

Cell Dysfunction ◽

T Cell Dysfunction

Cellular immunotherapeutic approaches such as chimeric antigen receptor (CAR) T-cell therapy in chronic lymphocytic leukemia (CLL) thus far have not met the high expectations. Therefore it is essential to better understand the molecular mechanisms of CLLinduced T-cell dysfunction. Even though a significant number of studies are available on T-cell function and dysfunction in CLL patients, none examine dysfunction at the epigenomic level. In non-malignant T-cell research, epigenomics is widely employed to define the differentiation pathway into T-cell exhaustion. Additionally, metabolic restrictions in the tumor microenvironment that cause T-cell dysfunction are often mediated by epigenetic changes. With this review paper we argue that understanding the epigenetic (dys)regulation in T cells of CLL patients should be leveled to the knowledge we currently have of the neoplastic B cells themselves. This will permit a complete understanding of how these immune cell interactions regulate T- and B-cell function. Here we relate the cellular and phenotypic characteristics of CLL-induced T-cell dysfunction to epigenetic studies of T-cell regulation emerging from chronic viral infection and tumor models. This paper proposes a framework for future studies into the epigenetic regulation of CLL-induced Tcell dysfunction, knowledge that will help to guide improvements in the utility of autologous T-cell based therapies in CLL.

Download Full-text

The Functions of ZIP8, ZIP14, and ZnT10 in the Regulation of Systemic Manganese Homeostasis

International Journal of Molecular Sciences ◽

10.3390/ijms21093304 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3304

Author(s):

James W.W. Winslow ◽

Kirsten H. Limesand ◽

Ningning Zhao

Keyword(s):

Antioxidant Defense ◽

Molecular Mechanisms ◽

Cell Function ◽

Immune Cell ◽

The Body ◽

Metal Transporters ◽

Cellular Processes ◽

The Past ◽

Genes Encoding ◽

Essential Nutrient

As an essential nutrient, manganese is required for the regulation of numerous cellular processes, including cell growth, neuronal health, immune cell function, and antioxidant defense. However, excess manganese in the body is toxic and produces symptoms of neurological and behavioral defects, clinically known as manganism. Therefore, manganese balance needs to be tightly controlled. In the past eight years, mutations of genes encoding metal transporters ZIP8 (SLC39A8), ZIP14 (SLC39A14), and ZnT10 (SLC30A10) have been identified to cause dysregulated manganese homeostasis in humans, highlighting the critical roles of these genes in manganese metabolism. This review focuses on the most recent advances in the understanding of physiological functions of these three identified manganese transporters and summarizes the molecular mechanisms underlying how the loss of functions in these genes leads to impaired manganese homeostasis and human diseases.

Download Full-text

A Functional Interplay between 5-Lipoxygenase andμ-Calpain Affects Survival and Cytokine Profile of Human Jurkat T Lymphocyte Exposed to Simulated Microgravity

BioMed Research International ◽

10.1155/2014/782390 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Valeria Gasperi ◽

Cinzia Rapino ◽

Natalia Battista ◽

Monica Bari ◽

Nicolina Mastrangelo ◽

...

Keyword(s):

T Lymphocyte ◽

Molecular Mechanisms ◽

Simulated Microgravity ◽

Cell Function ◽

Immune Cell ◽

Apoptotic Cell ◽

Immune Cell Function ◽

Space Flights ◽

Apoptotic Death ◽

Mammalian Tissues

A growing body of evidence strongly indicates that both simulated and authentic weightlessness exert a broad range of effects on mammalian tissues and cells, including impairment of immune cell function and increased apoptotic death. We previously reported that microgravity-dependent activation of 5-lipoxygenase (5-LOX) might play a central role in the initiation of apoptosis in human T lymphocytes, suggesting that the upregulation of this enzyme might be (at least in part) responsible for immunodepression observed in astronauts during space flights. Herein, we supplement novel information about the molecular mechanisms underlying microgravity-triggered apoptotic cell death and immune system deregulation, demonstrating that under simulated microgravity human Jurkat T cells increase the content of cytosolic DNA fragments and cytochrome c (typical hallmarks of apoptosis) and have an upregulated expression and activity ofµ-calpain. These events were paralleled by the unbalance of interleukin- (IL-) 2 and interferon- (INF-)γ, anti- and proapoptotic cytokines, respectively, that seemed to be dependent on the functional interplay between 5-LOX andµ-calpain. Indeed, we report unprecedented evidence that 5-LOX inhibition reduced apoptotic death, restored the initial IL-2/INF-γratio, and more importantly revertedµ-calpain activation induced by simulated microgravity.

Download Full-text

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

10.1101/083873 ◽

2016 ◽

Cited By ~ 1

Author(s):

Kyle Burrows ◽

Frann Antignano ◽

Michael Bramhall ◽

Alistair Chenery ◽

Sebastian Scheer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Vitamin A ◽

Molecular Mechanisms ◽

Cell Function ◽

Immune Cell ◽

Intestinal Inflammation ◽

Critical Role ◽

Central Component ◽

Food Antigens

ABSTRACTThe intestine is a unique immune environment that must respond to infectious organisms but remain tolerant to commensal microbes and food antigens. However, the molecular mechanisms that regulate immune cell function in the intestine remain unclear. Here we identify the POK/ZBTB family transcription factor Hypermethylated in cancer 1 (HIC1, ZBTB29) as a central component of immunity and inflammation in the intestine. HIC1 is specifically expressed in immune cells in the intestinal lamina propria (LP) in the steady state and mice with a T cell-specific deletion of HIC1 have reduced numbers of T cells in the LP. HIC1 expression is regulated by the Vitamin A metabolite retinoic acid, as mice raised on a Vitamin A-deficient diet lack HIC1-positive cells in the intestine. HIC1-deficient T cells overproduce IL-17A in vitro and in vivo, and fail to induce intestinal inflammation, identifying a critical role for HIC1 in the regulation of T cell function in the intestinal microenvironment under both homeostatic and inflammatory conditions.

Download Full-text

Mast cell activation is enhanced by Tim1:Tim4 interaction but not by Tim-1 antibodies

F1000Research ◽

10.12688/f1000research.8132.2 ◽

2016 ◽

Vol 5 ◽

pp. 251

Author(s):

Binh Phong ◽

Lawrence P. Kane

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Signaling Pathways ◽

Cell Activation ◽

Molecular Mechanisms ◽

Cell Function ◽

Immune Cell ◽

Allergic Diseases ◽

Mast Cell Activation ◽

High Affinity Ige Receptor

Polymorphisms in theT cell (or transmembrane) immunoglobulin and mucin domain 1(TIM-1) gene, particularly in the mucin domain, have been associated with atopy and allergic diseases in mice and human. Genetic- and antibody-mediated studies revealed that Tim-1 functions as a positive regulator of Th2 responses, while certain antibodies to Tim-1 can exacerbate or reduce allergic lung inflammation. Tim-1 can also positively regulate the function of B cells, NKT cells, dendritic cells and mast cells. However, the precise molecular mechanisms by which Tim-1 modulates immune cell function are currently unknown. In this study, we have focused on defining Tim-1-mediated signaling pathways that enhance mast cell activation through the high affinity IgE receptor (FceRI). Using a Tim-1 mouse model lacking the mucin domain (Tim-1Dmucin), we show for the first time that the polymorphic Tim-1 mucin region is dispensable for normal mast cell activation. We further show that Tim-4 cross-linking of Tim-1 enhances select signaling pathways downstream of FceRI in mast cells, including mTOR-dependent signaling, leading to increased cytokine production but without affecting degranulation.

Download Full-text

Mast cell activation is enhanced by Tim1:Tim4 interaction but not by Tim-1 antibodies

F1000Research ◽

10.12688/f1000research.8132.1 ◽

2016 ◽

Vol 5 ◽

pp. 251

Author(s):

Binh Phong ◽

Lawrence P. Kane

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Signaling Pathways ◽

Cell Activation ◽

Molecular Mechanisms ◽

Cell Function ◽

Immune Cell ◽

Allergic Diseases ◽

Mast Cell Activation ◽

High Affinity Ige Receptor

Polymorphisms in theT cell (or transmembrane) immunoglobulin and mucin domain 1(TIM-1) gene, particularly in the mucin domain, have been associated with atopy and allergic diseases in mice and human. Genetic- and antibody-mediated studies revealed that Tim-1 functions as a positive regulator of Th2 responses, while certain antibodies to Tim-1 can exacerbate or reduce allergic lung inflammation. Tim-1 can also positively regulate the function of B cells, NKT cells, dendritic cells and mast cells. However, the precise molecular mechanisms by which Tim-1 modulates immune cell function are currently unknown. In this study, we have focused on defining Tim-1-mediated signaling pathways that enhance mast cell activation through the high affinity IgE receptor (FceRI). Using a Tim-1 mouse model lacking the mucin domain (Tim-1Dmucin), we show for the first time that the polymorphic Tim-1 mucin region is dispensable for normal mast cell activation. We further show that Tim-4 cross-linking of Tim-1 enhances select signaling pathways downstream of FceRI in mast cells, including mTOR-dependent signaling, leading to increased cytokine production but without affecting degranulation.

Download Full-text

Schistosome immunomodulators

PLoS Pathogens ◽

10.1371/journal.ppat.1010064 ◽

2021 ◽

Vol 17 (12) ◽

pp. e1010064

Author(s):

Sreemoyee Acharya ◽

Akram A. Da’dara ◽

Patrick J. Skelly

Keyword(s):

Molecular Mechanisms ◽

Cell Function ◽

Immune Cell ◽

Cell Metabolism ◽

Natural Infection ◽

Host Cells ◽

Anionic Polymer ◽

Th2 Response ◽

Anti Inflammatory ◽

The Impact

Schistosomes are long lived, intravascular parasitic platyhelminths that infect >200 million people globally. The molecular mechanisms used by these blood flukes to dampen host immune responses are described in this review. Adult worms express a collection of host-interactive tegumental ectoenzymes that can cleave host signaling molecules such as the “alarmin” ATP (cleaved by SmATPDase1), the platelet activator ADP (SmATPDase1, SmNPP5), and can convert AMP into the anti-inflammatory mediator adenosine (SmAP). SmAP can additionally cleave the lipid immunomodulator sphingosine-1-phosphate and the proinflammatory anionic polymer, polyP. In addition, the worms release a barrage of proteins (e.g., SmCB1, SjHSP70, cyclophilin A) that can impinge on immune cell function. Parasite eggs also release their own immunoregulatory proteins (e.g., IPSE/α1, omega1, SmCKBP) as do invasive cercariae (e.g., Sm16, Sj16). Some schistosome glycans (e.g., LNFPIII, LNnT) and lipids (e.g., Lyso-PS, LPC), produced by several life stages, likewise affect immune cell responses. The parasites not only produce eicosanoids (e.g., PGE2, PGD2—that can be anti-inflammatory) but can also induce host cells to release these metabolites. Finally, the worms release extracellular vesicles (EVs) containing microRNAs, and these too have been shown to skew host cell metabolism. Thus, schistosomes employ an array of biomolecules—protein, lipid, glycan, nucleic acid, and more, to bend host biochemistry to their liking. Many of the listed molecules have been individually shown capable of inducing aspects of the polarized Th2 response seen following infection (with the generation of regulatory T cells (Tregs), regulatory B cells (Bregs) and anti-inflammatory, alternatively activated (M2) macrophages). Precisely how host cells integrate the impact of these myriad parasite products following natural infection is not known. Several of the schistosome immunomodulators described here are in development as novel therapeutics against autoimmune, inflammatory, and other, nonparasitic, diseases.

Download Full-text

Regulation of Immunity via Multipotent Mesenchymal Stromal Cells

Acta Naturae ◽

10.32607/20758251-2012-4-1-23-31 ◽

2012 ◽

Vol 4 (1) ◽

pp. 23-31 ◽

Cited By ~ 9

Author(s):

Yu. P. Rubtsov ◽

Yu. G. Suzdaltseva ◽

K. V. Goryunov ◽

N. I. Kalinina ◽

V. Yu. Sysoeva ◽

...

Keyword(s):

Autoimmune Diseases ◽

Mesenchymal Stromal Cells ◽

Immune Cells ◽

Stromal Cells ◽

Cell Activation ◽

Molecular Mechanisms ◽

Cell Function ◽

Immune Cell ◽

Nk Cell ◽

Multipotent Mesenchymal Stromal Cells

Immune cells responsible for inflammation development are involved in tissue damage caused by wounding and various pathologies. Control of immune cell activation could be of significant benefit for regenerative medicine and the treatment of patients with autoimmune and degenerative diseases. It is a proven fact that MCSs (multipotent mesenchymal stromal cells) are capable of suppressing immune responses via the inhibition of dendritic cell maturation and via the restraining of the T, B, and NK cell function in the course of autoimmune diseases and various forms of inflammation. MSCs can be isolated easily from almost every type of tissue or organ and subsequently expanded in vitro. These cells are self-renewable and can be differentiated into various cell types of mesenchymal lineage. The current review contains a collection and critical analysis of data regarding the molecular mechanisms responsible for cross-talk between immune cells and MSCs. Some of these mechanisms can be used for the development of new practical approaches for the treatment of autoimmune diseases.

Download Full-text

Hypoxemia in the absence of blood loss upregulates iNOS expression and activity in macrophages

AJP Cell Physiology ◽

10.1152/ajpcell.1999.276.2.c285 ◽

1999 ◽

Vol 276 (2) ◽

pp. C285-C290 ◽

Cited By ~ 35

Author(s):

Martin K. Angele ◽

Martin G. Schwacha ◽

Nadia Smail ◽

Robert A. Catania ◽

Alfred Ayala ◽

...

Keyword(s):

Blood Loss ◽

Cell Function ◽

Immune Cell ◽

Degradation Products ◽

Inos Expression ◽

Inos Mrna ◽

No Production ◽

Inos Activity ◽

Ifn Γ ◽

Expression And Activity

Regional hypoxia, associated with hemorrhage, is thought to induce a variety of alterations in immune cell function, including upregulation of macrophage-inducible nitric oxide synthase (iNOS) expression and activity (NO production). Furthermore, NO may cause immune cell dysfunction similar to that associated with hemorrhagic shock. However, it remains unknown whether hypoxia per se in the absence of any blood loss is a sufficient stimulus to cause iNOS expression and NO production by macrophages. To study this, male Sprague-Dawley rats (275–325 g) were placed in a plastic box flushed with a gas mixture containing 5% O2-95% N2 for 60 min. Peritoneal and splenic macrophages were isolated 0–5.5 h thereafter, and blood samples were obtained. Nitrite and nitrate (stable degradation products of NO) production by splenic and peritoneal macrophages cultured for 48 h was significantly increased 3 and 5.5 h after hypoxemia. The increase in NO production by macrophages was preceded by elevated expression of iNOS mRNA at 1.5 h after hypoxia. Additionally, interferon-γ (IFN-γ) levels in plasma from rats subjected to hypoxemia were significantly elevated soon after the insult (0–1.5 h posthypoxemia), suggesting a causal relationship between IFN-γ production and upregulation of iNOS activity. We propose that a hypoxemia-induced increase in macrophage iNOS activity following hemorrhage may in part be responsible for the observed immune dysfunction. Thus attempts to suppress macrophage iNOS activity after this form of trauma may be helpful in improving immune function under those conditions.

Download Full-text