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SOCS proteins also influence ERK (10), PI3K (11), Notch (12), MAPK (13), and NF-κB (14) signaling cascades that directs M1 and M2 functions. [...]SOCS1 mediates a negative feedback mechanism during TLR4 signaling, via control of both MyD88-dependent and MyD88-independent signaling. An elevated expression of SOCS1 is important for the arginase I-induced suppressive nature of M2 macrophages that attenuate lymphocyte proliferation (28). [...]SOCS1 regulates the iNOS/arginase I expression ratio in both M1 and M2 macrophages and helps fine-tune key signaling pathways to mount an appropriate response to changes within the microenvironment. [...]mice deficient in SOCS3 in myeloid cells are resistant to endotoxic shock (35) with reduced production of pro-inflammatory cytokines. The reasons for this discrepancy in findings are unclear but could relate to differences in dose and purity of the LPS used in the different studies, as well as and the genes and time-points analyzed after macrophage activation (7,35). [...]the conflicting results for the role of SOCS3 in M1 polarization in isolated macrophages in vitro (5–7) could result from the different technologies and species used (siRNA-mediated knockdown in rat and human macrophages, which avoids the risk of compensatory effects of other SOCS genes (5,6) versus cells from macrophage-specific SOCS3 knockout mice) (7).

Lawsonia intracellularis (LI) are obligate intracellular bacteria and the causative agent of proliferative hemorrhagic enteropathy that significantly impacts the health of piglets and the profitability of the swine industry. In this study, we used immunoinformatic and computational methodologies such as homology modelling, molecular docking, molecular dynamic (MD) simulation, and free energy calculations in a novel three stage approach to identify strong T and B cell epitopes in the LI proteome. From ∼ 1342 LI proteins, we narrowed our focus to 256 proteins that were either not well-identified (unknown role) or were expressed at a higher frequency in pathogenic strains relative to non-pathogenic strains. At stage 1, these proteins were analyzed for predicted virulence, antigenicity, solubility, and probability of residing within a membrane. At stage 2, we used NetMHCPan4-1 to identify over ten thousand cytotoxic T lymphocyte epitopes (CTLEs) and 286 CTLEs were ranked as having high predicted binding affinity for the SLA-1 and SLA-2 complexes. At stage 3, we used homology modeling to predict the structures of the top ranked CTLEs and we subjected each of them to molecular docking analysis with SLA-1*0401 and SLA-2*0402. The top ranked 25 SLA–CTLE complexes were selected to be an input for subsequent MD simulations to fully investigate the atomic-level dynamics of proteins under the natural thermal fluctuation of water and thus potentially provide deep insight into the CTLE-SLA interaction. We also performed free energy evaluation by Molecular Mechanics/Poisson−Boltzmann Surface Area to predict epitope interactions and binding affinities to the SLA-1 and SLA-2. We identified the top five CTLEs having the strongest binding energy to the indicated SLAs (-305.6 kJ/mol, -219.5 kJ/mol, -214.8 kJ/mol, -139.5 kJ/mol and -92.6 kJ/mol, respectively.) W also performed B-cell epitope prediction and the top-ranked 5 CTLEs and 3 B-cell epitopes were organized into a multi-epitope subunit antigen vaccine construct joined using EAAAK, AAY, KK, and GGGGG linkers with 40 residues of the LI DnaK protein attached to the N-terminus to further enhance the antigenicity of the vaccine construct. Blind docking studies showed strong interactions between our vaccine construct with swine Toll-like receptor 5. Collectively, these molecular modeling and immunoinformatic analyses present a useful in silico protocol for the discovery of candidate antigen in many viral and bacterial pathogens.

Vaccination continues to be a very important public health intervention to control infectious diseases in the world. Subunit vaccines are generally poorly immunogenic and require the addition of adjuvants to induce protective immune responses. Despite their critical role in vaccines, adjuvant mechanism of action remains poorly understood, which is a barrier to the development of new, safe and effective vaccines. In the present review, we focus on recent progress in understanding the mechanisms of action of the experimental adjuvants poly[di(carboxylatophenoxy)phosphazene] (PCPP) and poly[di(sodiumcarboxylatoethyl-phenoxy)phosphazene] (PCEP) (in this review, adjuvants PCPP and PCEP are collectively referred to as PZ denoting polyphosphazenes). PZs are high molecular weight, water-soluble, synthetic polymers that have been shown to regulate innate immune response genes, induce cytokines and chemokines secretion at the site of injection and, also, induce immune cell recruitment to the site of injection to create a local immune-competent environment. There is an evidence that as well as its role as an immunoadjuvant (that activate innate immune responses), PZ can also act as a vaccine carrier. The mechanism of action that explains how PZ leads to these effects is not known and is a barrier to the development of designer vaccines.

Protein misfolding and aggregation play crucial roles in amyloidogenic diseases through the self-assembly of intrinsically disordered proteins (IDPs) in type II diabetes (T2D), Alzheimer's disease (AD) and Parkinson’s disease (PD). PD is the most common neurodegenerative disorder after AD, and is associated with the loss of dopaminergic signaling, which causes motor and nonmotor signs and symptoms. Lewy bodies and Lewy neurites are common pathological hallmarks of PD that are mainly composed of aggregates of disordered α-synuclein (α-Syn). There have been many efforts to develop chemical compounds to prevent aggregation or facilitate disruption of the aggregates. Furthermore, the roles and interactions of many compounds have yet to be revealed at the atomistic level, especially their impacts on the dynamics and chain-chain interactions of the oligomers, which are of interest in this study. The conformational diversity and detailed interactions among homo-oligomer chains of α-Syn are not fully discovered; identifying these might help uncover a practical approach to developing a potent therapy. In this study, we used an in-silico investigation to address the conformational diversity of α-Syn oligomer. The roles of several point mutations in protein aggregation in PD are known; we take this further by evaluating the interaction energies and contributions of all residues in stability and residue-chain interactions. In this study, we docked chemical derivatives of three compounds with high drug-likeness properties to evaluate the roles of our ligands in the conformational dynamicity of the oligomers, with emphasis on intramolecular forces. Free energy evaluation of the modeled inter and intramolecular interactions through MD simulation shows effective interaction and binding between α-Syn and our compounds. However, we find that they do not significantly disrupt the chain-chain interactions, compared to unliganded simulation.

Bacteria do not simply express a constitutive panel of proteins but they instead undergo dynamic changes in their protein repertoire in response to changes in nutritional status and when exposed to different environments. These differentially expressed proteins may be suitable to use for vaccine antigens if they are virulence factors. Immediately upon entry into the host organism, bacteria are exposed to a different environment, which includes changes in temperature, osmotic pressure, pH, etc. Even when an organism has already penetrated the blood or lymphatics and it then enters another organ or a cell, it can respond to these new conditions by increasing the expression of virulence factors to aid in bacterial adherence, invasion, or immune evasion. Stress response proteins such as heat shock proteins and chaperones are some of the proteins that undergo changes in levels of expression and/or changes in cellular localization from the cytosol to the cell surface or the secretome, making them potential immunogens for vaccine development. Herein we highlight literature showing that intracellular chaperone proteins GroEL and DnaK, which were originally identified as playing a role in protein folding, are relocated to the cell surface or are secreted during invasion and therefore may be recognized by the host immune system as antigens. In addition, we highlight literature showcasing the immunomodulation effects these proteins can have on the immune system, also making them potential adjuvants or immunotherapeutics.

Protein tyrosine phosphatase 1B (PTP1B) is a non-receptor tyrosine phosphatase best known for its role in regulating insulin and leptin signalling. Recently, knowledge on the role of PTP1B as a major regulator of multiple signalling pathways involved in cell growth, proliferation, viability and metabolism has expanded, and PTP1B is recognised as a therapeutic target in several human disorders, including diabetes, obesity, cardiovascular diseases and hematopoietic malignancies. The function of PTP1B in the immune system was largely overlooked until it was discovered that PTP1B negatively regulates the Janus kinase—a signal transducer and activator of the transcription (JAK/STAT) signalling pathway, which plays a significant role in modulating immune responses. PTP1B is now known to determine the magnitude of many signalling pathways that drive immune cell activation and function. As such, PTP1B inhibitors are being developed and tested in the context of inflammation and autoimmune diseases. Here, we provide an up-to-date summary of the molecular role of PTP1B in regulating immune cell function and how targeting its expression and/or activity has the potential to change the outcomes of immune-mediated and inflammatory disorders.

Ageing research is establishing macrophages as key immune system regulators that undergo functional decline. Due to heterogeneity between species and tissue populations, a plethora of data exist and the power of scientific conclusions can vary substantially. This meta-analysis by information content (MAIC) and systematic literature review (SLR) aims to determine overall changes in macrophage gene and protein expression, as well as function, with age. PubMed was utilized to collate peer-reviewed literature relating to macrophage ageing. Primary studies comparing macrophages in at least two age groups were included. Data pertaining to gene or protein expression alongside method used were extracted for MAIC analysis. For SLR analysis, data included all macrophage-specific changes with age, as well as species, ontogeny and age of groups assessed. A total of 240 studies were included; 122 of which qualified for MAIC. The majority of papers focussed on changes in macrophage count/infiltration as a function of age, followed by gene and protein expression. The MAIC found iNOS and TNF to be the most commonly investigated entities, with 328 genes and 175 proteins showing consistent dysregulation with age across the literature. Overall findings indicate that cytokine secretion and phagocytosis are reduced and reactive oxygen species production is increased in the ageing macrophage. Collectively, our analysis identifies critical regulators in macrophage ageing that are consistently dysregulated, highlighting a plethora of targets for further investigation. Consistent functional changes with age found here can be used to confirm an ageing macrophage phenotype in specific studies and experimental models.

Background The prevalence of osteoarthritis (OA) increases with obesity, with up to two thirds of the elderly obese population affected by OA of the knee. The metabolic syndrome (MetS), frequently associated with central obesity and characterised by elevated waist circumference, raised fasting plasma glucose concentration, raised triglycerides, reduced high-density lipoproteins, and/or hypertension, is implicated in the pathogenesis of OA. This narrative review discusses the mechanisms involved in the influence of MetS on OA, with a focus on the effects on macrophages and chondrocytes. Main text A skewing of macrophages towards a pro-inflammatory M1 phenotype within synovial and adipose tissues is thought to play a role in OA pathogenesis. The metabolic perturbations typical of MetS are important drivers of pro-inflammatory macrophage polarisation and activity. This is mediated via alterations in the levels and activities of the cellular nutrient sensors 5′ adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1), intracellular accumulation of metabolic intermediates such as succinate and citrate, and increases in free fatty acids (FFAs) and hyperglycaemia-induced advanced glycation end-products (AGEs) that bind to receptors on the macrophage surface. Altered levels of adipokines, including leptin and adiponectin, further influence macrophage polarisation. The metabolic alterations in MetS also affect the cartilage through direct effects on chondrocytes by stimulating the production of pro-inflammatory and catabolic factors and possibly by suppressing autophagy and promoting cellular senescence. Conclusions The influence of MetS on OA pathogenesis involves a wide range of metabolic alterations that directly affect macrophages and chondrocytes. The relative burden of intra-articular versus systemic adipose tissue in the MetS-associated OA remains to be clarified. Understanding how altered metabolism interacts with joints affected by OA is crucial for the development of further strategies for treating this debilitating condition, such as supplementing existing therapies with metformin and utilising ω-3 fatty acid derivatives to restore imbalances in ω-3 and ω-6 fatty acids.

Summary Macrophages play a key role in tissue development and homeostasis, innate immune defence against microbes or tumours, and restoring homeostasis through tissue regeneration following infection or injury. The ability to adopt such diverse functions is due to their heterogeneous nature, which is driven largely by their developmental origin and their response to signals they encounter from the microenvironment. The most well-characterized signals driving macrophage phenotype and function are biochemical and metabolic. However, the way macrophages sense and respond to their extracellular biophysical environment is becoming increasingly recognized in the field of mechano-immunology. These biophysical cues can be signals from tissue components, such as the composition and charge of extracellular matrix or topography, elasticity, and stiffness of the tissue surrounding cells; and mechanical forces such as shear stress or stretch. Macrophages are important in determining whether a disease resolves or becomes chronic. Ageing and diseases such as cancer or fibrotic disorders are associated with significant changes in the tissue biophysical environment, and this provides signals that integrate with those from biochemical and metabolic stimuli to ultimately dictate the overall function of macrophages. This review provides a brief overview of macrophage polarization, followed by a selection of commonly recognized physiological and applied biophysical stimuli impacting macrophage activity, and the potential signalling mechanisms driving downstream responses. The effects of biophysical cues on macrophages’ function in homeostasis and disease and the associated clinical implications are also highlighted. Graphical Abstract Graphical Abstract

Immune privilege (IP), a term introduced to explain the unpredicted acceptance of allogeneic grafts by the eye and the brain, is considered a unique property of these tissues. However, immune responses are modified by the tissue in which they occur, most of which possess IP to some degree. The eye therefore displays a spectrum of IP because it comprises several tissues. IP as originally conceived can only apply to the retina as it contains few tissue-resident bone-marrow derived myeloid cells and is immunologically shielded by a sophisticated barrier – an inner vascular and an outer epithelial barrier at the retinal pigment epithelium. The vascular barrier comprises the vascular endothelium and the glia limitans. Immune cells do not cross the blood-retinal barrier (BRB) despite two-way transport of interstitial fluid, governed by tissue oncotic pressure. The BRB, and the blood-brain barrier (BBB) mature in the neonatal period under signals from the expanding microbiome and by 18 months are fully established. However, the adult eye is susceptible to intraocular inflammation (uveitis; frequency ~200/100,000 population). Uveitis involving the retinal parenchyma (posterior uveitis, PU) breaches IP, while IP is essentially irrelevant in inflammation involving the ocular chambers, uveal tract and ocular coats (anterior/intermediate uveitis/sclerouveitis, AU). Infections cause ~50% cases of AU and PU but infection may also underlie the pathogenesis of immune-mediated “non-infectious” uveitis. Dysbiosis accompanies the commonest form, HLA-B27–associated AU, while latent infections underlie BRB breakdown in PU. This review considers the pathogenesis of uveitis in the context of IP, infection, environment, and the microbiome.