Shared TIR enzymatic functions regulate cell death and immunity across the tree of life.

In the 20th century, researchers studying animal and plant signaling pathways discovered a protein domain that is shared across diverse innate immune systems: the Toll/interleukin-1/resistance gene (TIR) domain. The TIR domain is found in several protein architectures and was defined as an adaptor that mediates protein-protein interactions in animal innate immunity and developmental signaling pathways. However, studies of nerve degeneration in animals-and subsequent breakthroughs in plant, bacterial, and archaeal systems-revealed that TIR domains possess enzymatic activities. We provide a synthesis of TIR functions and the role of various related TIR enzymatic products in evolutionarily diverse immune systems. These studies may ultimately guide interventions that would span the tree of life, from treating human neurodegenerative disorders and bacterial infections to preventing plant diseases.

Immune Signaling Kinases in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disorder of motor neurons in adults, with a median survival of 3-5 years after appearance of symptoms, and with no curative treatment currently available. Frontotemporal dementia (FTD) is also an adult-onset neurodegenerative disease, displaying not only clinical overlap with ALS, but also significant similarities at genetic and pathologic levels. Apart from the progressive loss of neurons and the accumulation of protein inclusions in certain cells and tissues, both disorders are characterized by chronic inflammation mediated by activated microglia and astrocytes, with an early and critical impact of neurodegeneration along the disease course. Despite the progress made in the last two decades in our knowledge around these disorders, the underlying molecular mechanisms of such non-cell autonomous neuronal loss still need to be clarified. In particular, immune signaling kinases are currently thought to have a key role in determining the neuroprotective or neurodegenerative nature of the central and peripheral immune states in health and disease. This review provides a comprehensive and updated view of the proposed mechanisms, therapeutic potential, and ongoing clinical trials of immune-related kinases that have been linked to ALS and/or FTD, by covering the more established TBK1, RIPK1/3, RACK I, and EPHA4 kinases, as well as other emerging players in ALS and FTD immune signaling.

The role of Bruton's tyrosine kinase in the immune system and disease.

Bruton's tyrosine kinase (BTK) is a TEC kinase with a multifaceted role in B-cell biology and function, highlighted by its position as a critical component of the B-cell receptor signalling pathway. Due to its role as a therapeutic target in several haematological malignancies including chronic lymphocytic leukaemia, BTK has been gaining tremendous momentum in recent years. Within the immune system, BTK plays a part in numerous pathways and cells beyond B cells (i.e. T cells, macrophages). Not surprisingly, BTK has been elucidated to be a driving factor not only in lymphoproliferative disorders but also in autoimmune diseases and response to infection. To extort this role, BTK inhibitors such as ibrutinib have been developed to target BTK in other diseases. However, due to rising levels of resistance, the urgency to develop new inhibitors with alternative modes of targeting BTK is high. To meet this demand, an expanding list of BTK inhibitors is currently being trialled. In this review, we synopsize recent discoveries regarding BTK and its role within different immune cells and pathways. Additionally, we discuss the broad significance and relevance of BTK for various diseases ranging from haematology and rheumatology to the COVID-19 pandemic. Overall, BTK signalling and its targetable nature have emerged as immensely important for a wide range of clinical applications. The development of novel, more specific and less toxic BTK inhibitors could be revolutionary for a significant number of diseases with yet unmet treatment needs.

Loss of metabolic flexibility as a result of overexpression of pyruvate dehydrogenase kinases in muscle, liver and the immune system: Therapeutic targets in metabolic diseases.

Good health depends on the maintenance of metabolic flexibility, which in turn is dependent on the maintenance of regulatory flexibility of a large number of regulatory enzymes, but especially the pyruvate dehydrogenase complex (PDC), because of its central role in carbohydrate metabolism. Flexibility in regulation of PDC is dependent on rapid changes in the phosphorylation state of PDC determined by the relative activities of the pyruvate dehydrogenase kinases (PDKs) and the pyruvate dehydrogenase phosphatases. Inactivation of the PDC by overexpression of PDK4 contributes to hyperglycemia, and therefore the serious health problems associated with diabetes. Loss of regulatory flexibility of PDC occurs in other disease states and pathological conditions that have received less attention than diabetes. These include cancers, non-alcoholic fatty liver disease, cancer-induced cachexia, diabetes-induced nephropathy, sepsis and amyotrophic lateral sclerosis. Overexpression of PDK4, and in some situations, the other PDKs, as well as under expression of the pyruvate dehydrogenase phosphatases, leads to inactivation of the PDC, mitochondrial dysfunction and deleterious effects with health consequences. The possible basis for this phenomenon, along with evidence that overexpression of PDK4 results in phosphorylation of "off-target" proteins and promotes excessive transport of Ca2+ into mitochondria through mitochondria-associated endoplasmic reticulum membranes are discussed. Recent efforts to find small molecule PDK inhibitors with therapeutic potential are also reviewed.

Lysozyme is a component of the innate immune system linked to obesity associated-chronic low-grade inflammation and altered glucose tolerance.

BACKGROUND & AIMS: Several proteins of the innate immune system are known to be deregulated with insulin resistance. We here aimed to investigate the relationship among circulating lysozyme (both plasma concentration and activity) and obesity-associated metabolic disturbances. METHODS: Plasma lysozyme concentration was determined cross-sectionally in a discovery (Cohort 1, n = 137) and in a replication cohort (Cohort 2, n = 181), in which plasma lysozyme activity was also analyzed. Plasma lysozyme was also evaluated longitudinally in participants from the replication cohort (n = 93). Leukocyte lysozyme expression (LYZ mRNA) were also investigated in an independent cohort (Cohort 3, n = 76), and adipose tissue (AT) LYZ mRNA (n = 25) and plasma peptidoglycan levels (n = 61) in subcohorts from discovery cohort. RESULTS: Translocation of peptidoglycan (as inferred from its increased circulating levels) was linked to plasma lysozyme, hyperinsulinemia and dyslipidemia in obese subjects. In both discovery and replication cohorts, plasma lysozyme levels and activity were significantly increased in obesity in direct association with obesity-associated metabolic disturbances and inflammatory parameters, being circulating lysozyme negatively correlated with fasting glucose, HbA1c and insulin resistance (HOMA-IR) in obese subjects. Of note, total cholesterol (p < 0.0001) and LDL cholesterol (p = 0.003) contributed independently to age-, gender- and BMI adjusted plasma lysozyme activity. Longitudinally, changes in HbA1c levels and serum LDL cholesterol were negatively associated with circulating lysozyme antimicrobial activity. On the contrary, the change in glucose infusion rate during the clamp (insulin sensitivity) was positively associated with lysozyme concentration. CONCLUSIONS: Increased plasma lysozyme levels and activity are found in obese subjects. The longitudinal findings suggest that plasma lysozyme might be protective on the development of obesity-associated metabolic disturbances.

Optimization of tamoxifen-induced Cre activity and its effect on immune cell populations.

Tamoxifen (TAM) inducible Cre recombinase system is an essential tool to study gene function when early ablation or overexpression can cause developmental defects or embryonic lethality. However, there remains a lack of consensus on the optimal route and dosage of TAM administration in vivo. Here, we assessed dosage and delivery of TAM for activation of Cre in immune cell subsets assessed longitudinally and spatially using transgenic mice with ubiquitously expressed Cre/ER and the Cre-inducible fluorescent reporter YFP. After comparing two TAM delivery methods (intraperitoneal versus oral gavage) and different doses, we found that 3 mg of TAM administered orally for five consecutive days provides maximal reporter induction with minimal adverse effects in vivo. Serum levels of TAM peaked 1 week after initiating treatment then slowly decreased, regardless of dosing and delivery methods. TAM concentration in specific tissues (liver, spleen, lymph nodes, and thymus) was also dependent on delivery method and dose. Cre induction was highest in myeloid cells and B cells and substantially lower in T cells, and double-positive thymocytes had a notably higher response to TAM. In addition to establishing optimal dose and administration of TAM, our study reveals a disparate activity of Cre in different cell immune populations when using Cre/ER models.

Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues.

BACKGROUND: Since its discovery in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 2 180 000 people worldwide and has caused more than 150 000 deaths as of April 16, 2020. SARS-CoV-2, which is the virus causing coronavirus disease 2019 (COVID-19), uses the angiotensin-converting enzyme 2 (ACE2) as a cell receptor to invade human cells. Thus, ACE2 is the key to understanding the mechanism of SARS-CoV-2 infection. This study is to investigate the ACE2 expression in various human tissues in order to provide insights into the mechanism of SARS-CoV-2 infection. METHODS: We compared ACE2 expression levels across 31 normal human tissues between males and females and between younger (ages ≤ 49 years) and older (ages > 49 years) persons using two-sided Student's t test. We also investigated the correlations between ACE2 expression and immune signatures in various tissues using Pearson's correlation test. RESULTS: ACE2 expression levels were the highest in the small intestine, testis, kidneys, heart, thyroid, and adipose tissue, and were the lowest in the blood, spleen, bone marrow, brain, blood vessels, and muscle. ACE2 showed medium expression levels in the lungs, colon, liver, bladder, and adrenal gland. ACE2 was not differentially expressed between males and females or between younger and older persons in any tissue. In the skin, digestive system, brain, and blood vessels, ACE2 expression levels were positively associated with immune signatures in both males and females. In the thyroid and lungs, ACE2 expression levels were positively and negatively associated with immune signatures in males and females, respectively, and in the lungs they had a positive and a negative correlation in the older and younger groups, respectively. CONCLUSIONS: Our data indicate that SARS-CoV-2 may infect other tissues aside from the lungs and infect persons with different sexes, ages, and races equally. The different host immune responses to SARS-CoV-2 infection may partially explain why males and females, young and old persons infected with this virus have markedly distinct disease severity. This study provides new insights into the role of ACE2 in the SARS-CoV-2 pandemic.

Effects of different dietary carbohydrate-to-lipid ratios on growth, plasma biochemical indexes, digestive, and immune enzymes activities of sub-adult orange-spotted grouper Epinephelus coioides.

A 10-week feeding trial was conducted to investigate the effects of dietary carbohydrate-to-lipid (CHO:L) ratios on glycogen content, hematological indices, liver, and intestinal enzyme activity of sub-adult grouper Epinephelus coioides. Five iso-nitrogenous (496.0 g kg-1 protein) and iso-energetic (21.6 KJ g-1 gross energy) diets with varying CHO: L ratios of 0.65 (D1), 1.31 (D2), 2.33 (D3), 4.24 (D4), and 8.51 (D5), respectively, were fed to triplicate groups of 20 fish (average 275.1 ± 1.86 g). Results showed that the weight gain rate (WGR), specific growth rate (SGR), and protein efficiency ratio (PER) of sub-adult grouper increased and then stable when dietary CHO:L ratios reach D4 (CHO:L = 4.24). The trend of feed conversion ratio (FCR) was opposite to PER. Along with the dietary CHO:L ratios, the liver and muscle glycogen level increased gradually. Plasma triglycerides (TG) and glucose (GLU) were all maximized at D5 (CHO:L = 8.51) group, cholesterol (CHOL) at D4 (CHO:L = 4.24) group. Digestive enzyme activities were significantly affected by dietary CHO:L ratios. Liver hexokinase (HK), alkaline phosphatase (AKP), and glucose-6-phosphate dehydrogenase (G6PDH) activity increased significantly as CHO:L ratios increased. Liver lysozyme (LYZ) and superoxide dismutase (SOD) activity of sub-adult grouper fed the D4 diet was significantly higher than that of the D2 (CHO:L = 1.31) diet. The trend of acid phosphatase (ACP) is opposite to AKP. The regression model analysis showed that the most suitable dietary CHO:L ratio to reach the highest SGR is 6.06.

NF-κB, IκB, and IKK: Integral Components of Immune System Signaling.

The NF-κB (Nuclear Factor kappa B) transcription factor plays crucial roles in the regulation of numerous biological processes including development of the immune system, inflammation, and innate and adaptive immune responses. Control over the immune cell functions of NF-κB results from signaling through one of two different routes: the canonical and noncanonical NF-κB signaling pathways. Present at the end of both pathways are the proteins NF-κB, IκB, and the IκB kinase (IKK). These proteins work together to deliver the myriad outcomes that influence context-dependent transcriptional control in immune cells. In the present chapter, we review the structural information available on NF-κB, IκB, and IKK, the critical terminal components of the NF-κB signaling, in relation to their physiological function.

The immunometabolic role of indoleamine 2,3-dioxygenase in atherosclerotic cardiovascular disease: immune homeostatic mechanisms in the artery wall.

Coronary heart disease and stroke, the two most common cardiovascular diseases worldwide, are triggered by complications of atherosclerosis. Atherosclerotic plaques are initiated by a maladaptive immune response triggered by accumulation of lipids in the artery wall. Hence, disease is influenced by several non-modifiable and modifiable risk factors, including dyslipidaemia, hypertension, smoking, and diabetes. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the kynurenine pathway of tryptophan (Trp) degradation, is modulated by inflammation and regarded as a key molecule driving immunotolerance and immunosuppressive mechanisms. A large body of evidence indicates that IDO-mediated Trp metabolism is involved directly or indirectly in atherogenesis. This review summarizes evidence from basic and clinical research showing that IDO is a major regulatory enzyme involved in the maintenance of immunohomeostasis in the vascular wall, as well as current knowledge about promising targets for the development of new anti-atherosclerotic drugs.

Nutrients, immune system, and exercise: Where will it take us?

The immune system plays a key role in controlling infections, repairing injuries, and restoring homeostasis. Immune cells are bioenergetically expensive during activation, which requires a tightly regulated control of the metabolic pathways, which is mostly regulated by two cellular energy sensors: Adenosine monophosphate-activated protein kinase and mammalian target of rapamycin. The activation and inhibition of this pathways can change cell subtype differentiation. Exercise intensity and duration and nutrient availability (especially glucose and glutamine) tightly regulate immune cell differentiation and function through Adenosine monophosphate-activated protein kinase and mammalian target of rapamycin signaling. Herein, we discuss the innate and adaptive immune-cell metabolism and how they can be affected by exercise and nutrients.

Lysosomal Acid Lipase: From Cellular Lipid Handler to Immunometabolic Target.

Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CEs) and triglycerides (TGs) to free cholesterol (FC) and free fatty acids (FFAs), which are then used for metabolic purposes in the cell. The process also occurs in immune cells that adapt their metabolic machinery to cope with the different energetic requirements associated with cell activation, proliferation, and polarization. LAL deficiency (LALD) causes severe lipid accumulation and affects the immunometabolic signature in animal models. In humans, LAL deficiency is associated with a peculiar clinical immune phenotype, secondary hemophagocytic lymphohistiocytosis. These observations suggest that LAL might play an important role in cellular immunometabolic modulation, and availability of an effective enzyme replacement strategy makes LAL an attractive target to rewire the metabolic machinery of immune cells beyond its role in controlling cellular lipid metabolism.

RNA m6 A modification enzymes shape innate responses to DNA by regulating interferon ß.

Modification of mRNA by N6-adenosine methylation (m6A) on internal bases influences gene expression in eukaryotes. How the dynamic genome-wide landscape of m6A-modified mRNAs impacts virus infection and host immune responses remains poorly understood. Here, we show that type I interferon (IFN) production triggered by dsDNA or human cytomegalovirus (HCMV) is controlled by the cellular m6A methyltrasferase subunit METTL14 and ALKBH5 demethylase. While METTL14 depletion reduced virus reproduction and stimulated dsDNA- or HCMV-induced IFNB1 mRNA accumulation, ALKBH5 depletion had the opposite effect. Depleting METTL14 increased both nascent IFNB1 mRNA production and stability in response to dsDNA. In contrast, ALKBH5 depletion reduced nascent IFNB1 mRNA production without detectably influencing IFN1B mRNA decay. Genome-wide transcriptome profiling following ALKBH5 depletion identified differentially expressed genes regulating antiviral immune responses, while METTL14 depletion altered pathways impacting metabolic reprogramming, stress responses, and aging. Finally, we determined that IFNB1 mRNA was m6A-modified within both the coding sequence and the 3' untranslated region (UTR). This establishes that the host m6A modification machinery controls IFNß production triggered by HCMV or dsDNA. Moreover, it demonstrates that responses to nonmicrobial dsDNA in uninfected cells, which shape host immunity and contribute to autoimmune disease, are regulated by enzymes controlling m6A epitranscriptomic changes.

Diverse functions of protein tyrosine phosphatase σ in the nervous and immune systems.

Tyrosine phosphorylation is a common means of regulating protein functions and signal transduction in multiple cells. Protein tyrosine phosphatases (PTPs) are a large family of signaling enzymes that remove phosphate groups from tyrosine residues of target proteins and change their functions. Among them, receptor-type PTPs (RPTPs) exhibit a distinct spatial pattern of expression and play essential roles in regulating neurite outgrowth, axon guidance, and synaptic organization in developmental nervous system. Some RPTPs function as essential receptors for chondroitin sulfate proteoglycans that inhibit axon regeneration following CNS injury. Interestingly, certain RPTPs are also important to regulate functions of immune cells and development of autoimmune diseases. PTPσ, a RPTP in the LAR subfamily, is expressed in various immune cells and regulates their differentiation, production of various cytokines and immune responses. In this review, we highlight the physiological and pathological significance of PTPσ and related molecules in both nervous and immune systems.

MAPK p38 regulates inflammatory gene expression via tristetraprolin: Doing good by stealth.

Tristetraprolin (TTP) is an RNA-destabilizing protein that exerts profound anti-inflammatory effects by inhibiting the expression of tumour necrosis factor and many other inflammatory mediators. The mitogen-activated protein kinase (MAPK) p38 signaling pathway controls the strength and duration of inflammatory responses by regulating both the expression and function of TTP. The kinase MK2 (MAPK activated kinase 2) is activated by MAPK p38, and in turn phosphorylates TTP at two critical serine residues. One consequence of these phosphorylations is the protection of TTP from proteasome-mediated degradation. Another consequence is the loss of mRNA destabilizing activity. The control of TTP expression and function by the MAPK p38 pathway provides an elegant mechanism for coupling the on and off phases of inflammatory responses, and dictating the precise kinetics of expression of individual inflammatory mediators.

The regulation effect of AMPK in immune related diseases.

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a key role in energetic metabolism regulation. Metabolic changes in immune cells, such as dendritic cell (DC), macrophages, neutrophils and lymphocytes that participate in the signal directed programs that promote or inhibit immune mediated diseases, including cancer, atherosclerosis and inflammatory diseases. Multiple pathogenic mechanisms are involved in the initiation and progression of disease, and many pathways have been uncovered. The mechanistic overlap in the metabolic changes and inflammation could indicate that some of the targets they have are in common, whereas AMPK could be useful in treatment of both disorders. The insight into identification of AMPK responsible for specific immune regulation, anti-inflammatory actions and understanding of the underlying molecular mechanism will promote the generation of novel AMPK activators, and provide novel therapy strategy.

Phospholipases: at the crossroads of the immune system and the pathogenesis of HIV-1 infection.

Multiple host factors and their interactions with viral proteins contribute to the complexity of HIV-1 pathogenesis and disease progression. The virus exploits the cell-signaling networks to prepare the ground for viral replication, to affect functions of either infected or uninfected bystander cells, and to evade the immune response. These events are hallmarks of HIV-1 pathogenesis that lead toward AIDS. Phospholipases are essential mediators of intracellular and intercellular signaling. They function as phospholipid-hydrolyzing enzymes, generating many bioactive lipid mediators or second messengers, which control multiple cellular functions, thus regulating a variety of physiologic and pathophysiologic processes. These enzymes also represent important components of the cell-signaling networks exploited by HIV-1 and its proteins to favor viral replication and persistence, as well as immune response dysfunction. Although some individual phospholipases were studied in the context of HIV-1 infection, the mechanisms whereby they regulate diverse infection-associated processes, as well as the interaction among different phospholipases have yet to be fully elucidated. In this review, we discuss the principal aspects of the complex interaction between phospholipases, HIV-1, and the immune system. A thorough understanding of the signaling networks that involve phospholipases in both HIV-1-infected cells and individuals is essential to determine whether therapeutic targeting of these enzymes may represent a novel approach to control viral replication, as well as the associated inflammation and comorbidities.

Natural environmental impacts on teleost immune function.

The environment in which teleosts exist can experience considerable change. Short-term changes can occur in relation to tidal movements or adverse weather events. Long-term changes can be caused by anthropogenic impacts such as climate change, which can result in changes to temperature, acidity, salinity and oxygen capacity of aquatic environments. These changes can have important impacts on the physiology of an animal, including its immune system. This can have consequences on the well-being of the animal and its ability to protect against pathogens. This review will look at recent investigations of these types of environmental change on the immune response in teleosts.

[Heme oxygenase-1 - more than the cytoprotection]. / Oksygenaza hemowa-4 - wiecej niz cytoprotekcja.

Heme oxygenase-1 (HO-1) is an enzyme degrading heme to three products - ferrous ions, carbon monoxide and biliverdin. Its function extends, however, far beyond removal of pro-oxidative heme from microenvironment. During the last few decades it was proven that apart from cytoprotective and antioxidative properties HO-1 regulates also a variety of cellular processes. It exerts an impact on both innate and adaptive immune response. HO-1 accelerates development of new blood vessels in a process called angiogenesis. Moreover, it controls cell cycle and depending on a cell type increases or decreases the rate of cell division. Finally, the most recent data indicate, that HO-1 regulates also differentiation of various stem and progenitor cells. Interestingly, that aspect of HO-1 function seems also to depend on cell type. In this review, both effects and mechanisms of above-mentioned processes in different cell types are discussed.

Immunostimulant and chemoprotective effect of vivartana, a polyherbal formulation against cyclophosphamide induced toxicity in Swiss albino mice.

The aim of the study is to develop a technology for cost effective immunomodulator from natural products to combat adverse effects during cancer chemotherapy. In the present study, the immunomodulatory efficacy of Vivartana, a poly herbal formulation in immunosuppressed animal model induced by cyclophosphamide (CTX) and its comparison with standard herbal immunostimulators Chyawanprash and Brahma Rasayana was investigated. The effect of Vivartana (500 mg/kg x bw) (p.o.), Chyawanprash (20 mg/kg.bw) (p.o.) and Brahma Rasayana (20 mg/kg x bw) (p.o.) on hematological parameters, relative organ weight, Bone marrow cellularity and α-esterase activity were determined in Swiss albino mice by using the standard methods. Among the herbal formulations Vivartana showed the maximum number of leukocytes (13150 cells/mm3) on the 15th day. The leukocyte count in Vivartana treated CTX induced group shows significant increase (5375 cells/mm3) when compared with CTX alone induced group (3358 cells/mm3) on the same day. The Vivartana treated CTX induced group shows increase in the hemoglobin level compared with the CTX induced group. Moreover, Vivartana treatment prevented the loss of organ weight in the CTX induced group by the enhancement of spleenocytes on the 7th day and thymocytes on the 11th day. Similarly the lowered bone marrow cellularity and number of α-esterase positive cells in CTX induced group were restored in the Vivartana treatment. Treatment with vivartana also exhibits hepatoprotective activity by regulating the SGOT and SGPT levels in CTX induced group. The study indicates that Vivartana has the considerable potential as an immunostimulant and chemoprotectant against CTX induced immunosuppression in Swiss albino mice.