Immunometabolism in bladder cancer microenvironment

The initiation and progression of bladder cancer (BC), is dependent on its tumor microenvironment (TME). On the other hand, cancer cells shape and train TME to support their development, respond to treatment and migration in an organism. Immune cells exert key roles in the BC microenvironment and have complex interactions with BC cells. These complicated interplays result in metabolic competition in the TME leading to nutrient deprivation, acidosis, hypoxia and metabolite accumulation, which impair immune cell function. Recent studies have demonstrated that immune cells functions are closely correlated with their metabolism. Immunometabolism describes the functional metabolic alterations that take place within immune cells and the role of these cells in directing metabolism and immune response in tissues or diseases such as cancer. Some molecules and their metabolites in the TME including glucose, fatty acids and amino acids can regulate the phenotype, function and metabolism of immune cells. Hence, here we describe some recent advances in immunometabolism and relate them to BC progression. A profound understanding of the metabolic reprogramming of BC cells and immune cells in the TME will offer novel opportunities for targeted therapies in future.

Alpha-2-Macroglobulin in Inflammation, Immunity and Infections

Alpha-2-macroglobulin is an extracellular macromolecule mainly known for its role as a broad-spectrum protease inhibitor. By presenting itself as an optimal substrate for endopeptidases of all catalytic types, alpha-2-macroglobulin lures active proteases into its molecular cage and subsequently ‘flags’ their complex for elimination. In addition to its role as a regulator of extracellular proteolysis, alpha-2-macroglobulin also has other functions such as switching proteolysis towards small substrates, facilitating cell migration and the binding of cytokines, growth factors and damaged extracellular proteins. These functions appear particularly important in the context of immune-cell function. In this review manuscript, we provide an overview of all functions of alpha-2-macroglobulin and place these in the context of inflammation, immunity and infections.

RNA2Immune: A Manually Curated Database of Experimentally Supported Data Linking Noncoding RNA Regulation to the Immune System

Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), have emerged as important regulators of the immune system and are involved in the control of immune cell biology, disease pathogenesis as well as vaccine responses. A repository of ncRNA−immune associations will facilitate our understanding of ncRNA-dependent mechanisms in the immune system and advance the development of therapeutics for immune disorders as well as vaccines. Here, we describe a comprehensive database, RNA2Immune, which aims to provide a high-quality resource of experimentally supported database linking ncRNA regulatory mechanisms to immune cell function, immune disease, cancer immunology, and vaccines. The current version of RNA2Immune documents 50,433 immune−ncRNA associations in 42 host species, including: (i) 6690 ncRNA associations with immune functions involving 31 immune cell types; (ii) 38,672 ncRNA associations with 348 immune diseases; (iii) 4833 ncRNA associations with cancer immunology; and (iv) 238 ncRNA associations with vaccine responses involving 26 vaccine types targeting 22 diseases. RNA2Immune provides a user-friendly interface for browsing, searching and downloading ncRNA−immune system associations. Collectively, RNA2Immune provides important information about how ncRNAs influence immune cell function, the pathological consequences of dysregulation of these ncRNAs (immune diseases and cancers), and how ncRNAs affect immune responses to vaccines. RNA2Immune is available at http://bio-bigdata.hrbmu.edu.cn/rna2immune/home.jsp.

198 Effect of Saccharomyces Cerevisiae Fermentate on Immune Cell Function Following Prolonged Head Elevation in 2-year-old Horses in Training

Horses are often restricted from lowering their heads while being transported, which prevents nasal drainage and triggers upper respiratory tract inflammation. Based on positive outcomes in other species, we hypothesized Saccharomyces cerevisiae fermentate (SCF) would modify this immune response in horses. Two-year-old Quarter Horses (mean ± SEM; initial age 22 ± 0.3 mo and BW 439 ± 3 kg) were randomly assigned to receive SCF (Diamond V, Cedar Rapids, IA; 21 g/d; n = 10) or no supplement (CON; n = 10) added to their diet (60% hay, 40% concentrate) for 60 d. Horses were exercised 4 d/wk for 30–45 min/d at light to moderate intensity. On d 57 horses were tethered with their heads elevated 35 cm above wither height for 12 h to mimic long-distance transport. Whole blood samples were obtained before and up to 72 h after stress induction to evaluate immune cell function. Data were compared using mixed model ANOVA with repeated measures. Serum cortisol (P < 0.01) and blood leukocytes (P < 0.05) were greater after head elevation. Lymphocyte proliferation in response to lipopolysaccharide was lower (P < 0.01) following head elevation but did not differ by treatment. Lymphocyte proliferation in response to concanavalin A exhibited a time × treatment effect (P = 0.05) where it decreased in CON horses after head elevation (P < 0.05) but was unchanged in SCF horses. Neutrophil phagocytosis of Streptococcus equi (a respiratory pathogen) was temporarily reduced (P < 0.05) after head elevation in both treatments. A time × treatment effect (P = 0.05) was observed for phagocytosis-induced oxidative burst, where it increased in SCF (P < 0.01) but did not change in CON horses. These data indicate SCF modified peripheral immune cell activity following a localized mucosal stressor. Whether these responses improve resistance to opportunistic pathogens following transport needs to be determined.

Immunosuppressive Roles of Galectin-1 in the Tumor Microenvironment

Evasion of immune surveillance is an accepted hallmark of tumor progression. The production of immune suppressive mediators by tumor cells is one of the major mechanisms of tumor immune escape. Galectin-1 (Gal-1), a pivotal immunosuppressive molecule, is expressed by many types of cancer. Tumor-secreted Gal-1 can bind to glycosylated receptors on immune cells and trigger the suppression of immune cell function in the tumor microenvironment, contributing to the immune evasion of tumors. The aim of this review is to summarize the current literature on the expression and function of Gal-1 in the human tumor microenvironment, as well as therapeutics targeting Gal-1.

Acid-Sensing Ion Channels: Expression and Function in Resident and Infiltrating Immune Cells in the Central Nervous System

Peripheral and central immune cells are critical for fighting disease, but they can also play a pivotal role in the onset and/or progression of a variety of neurological conditions that affect the central nervous system (CNS). Tissue acidosis is often present in CNS pathologies such as multiple sclerosis, epileptic seizures, and depression, and local pH is also reduced during periods of ischemia following stroke, traumatic brain injury, and spinal cord injury. These pathological increases in extracellular acidity can activate a class of proton-gated channels known as acid-sensing ion channels (ASICs). ASICs have been primarily studied due to their ubiquitous expression throughout the nervous system, but it is less well recognized that they are also found in various types of immune cells. In this review, we explore what is currently known about the expression of ASICs in both peripheral and CNS-resident immune cells, and how channel activation during pathological tissue acidosis may lead to altered immune cell function that in turn modulates inflammatory pathology in the CNS. We identify gaps in the literature where ASICs and immune cell function has not been characterized, such as neurotrauma. Knowledge of the contribution of ASICs to immune cell function in neuropathology will be critical for determining whether the therapeutic benefits of ASIC inhibition might be due in part to an effect on immune cells.