Novel Targeted Therapies for Rheumatoid Arthritis Based on Intracellular Signalling and Immunometabolic Changes: A Narrative Review.

Rheumatoid arthritis (RA) is a relatively common systemic autoimmune disease with an estimated prevalence of approximately 1% worldwide. Patients present predominantly with symmetrical small joint inflammatory arthritis, which involves dysregulated immune responses, leading to bone and cartilage deformities due to extensive erosive damage. The introduction of biological based therapies for the management of this life-altering condition, over the past three decades, has led to marked improvements in patients' quality of life. A wide range of both innate and adaptive immune cells are involved in the pathogenesis of RA, with a complex interplay of cytokines, T-cells, B-cells, and dendritic cells. Some of these cells have been successfully targeted in the treatment of RA by the use of biologics-based therapies. For example, rituximab therapy blocks B cell activation and abatacept effectively blocks T cell activation in patients with RA. Despite these advances, there remain some patients who are resistant to all current therapeutic options, which has encouraged further research into understanding the primary signal transduction pathways that mediate the disease. In this review we discuss the roles of the main signalling pathways, including metabolic reprogramming that have been implicated in RA disease progression, in order to develop a conceptual framework for more precise deployment of existing therapies, and to provide a rationale for producing molecular inhibitors of these pathways. Improved knowledge of the many intracellular signalling pathways in RA will complement current precision medicine strategies, particularly for the patients with difficult-to-treat RA, and especially in those with multidrug resistance disease.

"Input/output cytokines" in epidermal keratinocytes and the involvement in inflammatory skin diseases.

Considering the role of epidermal keratinocytes, they occupy more than 90% of the epidermis, form a physical barrier, and also function as innate immune barrier. For example, epidermal keratinocytes are capable of recognizing various cytokines and pathogen-associated molecular pattern, and producing a wide variety of inflammatory cytokines, chemokines, and antimicrobial peptides. Previous basic studies have shown that the immune response of epidermal keratinocytes has a significant impact on inflammatory skin diseases. The purpose of this review is to provide foundation of knowledge on the cytokines which are recognized or produced by epidermal keratinocytes. Since a number of biologics for skin diseases have appeared, it is necessary to fully understand the relationship between epidermal keratinocytes and the cytokines. In this review, the cytokines recognized by epidermal keratinocytes are specifically introduced as "input cytokines", and the produced cytokines as "output cytokines". Furthermore, we also refer to the existence of biologics against those input and output cytokines, and the target skin diseases. These use results demonstrate how important targeted cytokines are in real skin diseases, and enhance our understanding of the cytokines.

Potential of Interleukin (IL)-12 Group as Antivirals: Severe Viral Disease Prevention and Management.

The interleukin (IL)-12 family consists of pro- and anti-inflammatory cytokines that are able to signal the activation of host antiviral immunity while preventing over-reactive immune reactions due to active virus replication and viral clearance. Amongst others, IL-12 and IL-23 are produced and released by innate immune cells such as monocytes and macrophages to signal the proliferation of T cells and release of effector cytokines, which subsequently activate host defence against virus infections. Interestingly, the dualities of IL-27 and -35 are evidently shown in the course of virus infections; they regulate the synthesis of cytokines and antiviral molecules, proliferation of T cells, and viral antigen presentation in order to maximize virus clearance by the host immune system. In terms of anti-inflammatory reactions, IL-27 signals the formation of regulatory T cells (Treg) which in turn secrete IL-35 to control the scale of inflammatory response that takes place during virus infections. Given the multitasking of the IL-12 family in regards to the elimination of virus infections, its potential in antiviral therapy is unequivocally important. Thus, this work aims to delve deeper into the antiviral actions of the IL-12 family and their applications in antiviral therapies.

High-intensity interval training (treadmill) effects in myokines and endoplasmic reticulum stress of calf muscles in obese mice / Efectos del entrenamiento interválico de alta intensidad (trotadora) en miocinas y estrés del retículo endoplasmático de los músculos surales en ratones obesos

SUMMARY: Obesity is commonly associated with chronic tissue inflammation and skeletal muscle dysfunction. The study aimed to investigate the effects of High-Intensity Interval training (HIIT) on myokines and endoplasmic reticulum (ER) stress of diet- induced obese (DIO) mice. Three-month-old C57BL/6 male mice were fed a control (C) diet (n=20) or a high-fat (HF) diet (n=20) for 16 weeks. Then, half of the groups underwent HIIT (treadmill running) for an additional four weeks. HIIT increased calf muscles' contribution to BW (+24 %) and reduced weight gain in HF/HIIT than in HF (-120 %). Intramuscular fat accumulation was observed in HF and HF/ HIIT. Peak velocity was higher in HF/HIIT compared to HF (+26 %). Plasma insulin did not change, but glycemia was lower in HF/HIIT than in HF (-30 %). Fndc5 (+418 %) and Irisin (+72 %) were higher in HF/HIIT than in HF. Muscle Fgf21 was higher in HF/HIIT compared to HF (+30 %). In addition, NfKb (-53 %) and Tnfa (-63 %) were lower in HF/HIIT than in HF. However, Il1b (-86 %), Il6 (- 48 %), Il7 (-76 %), and Il15 (-21 %) were lower in HF/HIIT than in HF. Finally, HIIT reduced ER stress in HF/HIIT compared to HF: Atf4, -61 %; Chop, -61 %; Gadd45, -95 %. In conclusion, HIIT leads to weight loss and avoids muscle depletion. HIIT improves blood glucose, Irisin-Fndc5, and peak velocity. In addition, HIIT mitigates muscle inflammation and ER stress.

La obesidad es asociada comúnmente con inflamación tisular crónica y disfunción del músculo esquelético. El estudio tuvo como objetivo investigar los efectos del entrenamiento de intervalos de alta intensidad (HIIT) en las mioquinas y el estrés del retículo endoplásmico (ER) de ratones obesos inducidos por dieta (DIO). Se alimentó a ratones macho C57BL/6 de tres meses de edad con una dieta control (C) (n=20) o una dieta rica en grasas (HF) (n=20) durante 16 semanas. Luego, la mitad de los grupos se sometieron a HIIT (carrera en una trotadora) durante cuatro semanas más. HIIT aumentó la contribución de los músculos de la pantorrilla al BW (+24 %) y redujo el aumento de peso en HF/HIIT en HF (-120 %). Se observó acumulación de grasa intramuscular en HF y HF/HIIT. La velocidad máxima fue mayor en HF/HIIT en comparación con HF (+26 %). La insulina plasmática no cambió, pero la glucemia fue menor en HF/HIIT que en HF (-30 %). Fndc5 (+418 %) e Irisin (+72 %) fueron mayores en HF/HIIT que en HF. El Fgf21 muscular fue mayor en HF/ HIIT en comparación con HF (+30 %). Además, NfKb (-53 %) y Tnfa (-63 %) fueron menores en HF/HIIT que en HF. Sin embar- go, Il1b (-86 %), Il6 (-48 %), Il7 (-76 %) e Il15 (-21 %) fueron más bajos en HF/HIIT que en HF. Finalmente, HIIT redujo el estrés de RE en HF/HIIT en comparación con HF: Atf4, -61 %; Picar, - 61 %; Gadd45, -95 %. En conclusión, HIIT conduce a la pérdida de peso y evita el agotamiento muscular. HIIT mejora la glucosa en sangre, Irisin-Fndc5 y la velocidad máxima. Además, HIIT mitiga la inflamación muscular y el estrés ER.

Activation of Mast Cells by Neuropeptides: The Role of Pro-Inflammatory and Anti-Inflammatory Cytokines.

Mast cells (MCs) are tissue cells that are derived from bone marrow stem cells that contribute to allergic reactions, inflammatory diseases, innate and adaptive immunity, autoimmunity, and mental disorders. MCs located near the meninges communicate with microglia through the production of mediators such as histamine and tryptase, but also through the secretion of IL-1, IL-6 and TNF, which can create pathological effects in the brain. Preformed chemical mediators of inflammation and tumor necrosis factor (TNF) are rapidly released from the granules of MCs, the only immune cells capable of storing the cytokine TNF, although it can also be produced later through mRNA. The role of MCs in nervous system diseases has been extensively studied and reported in the scientific literature; it is of great clinical interest. However, many of the published articles concern studies on animals (mainly rats or mice) and not on humans. MCs are known to interact with neuropeptides that mediate endothelial cell activation, resulting in central nervous system (CNS) inflammatory disorders. In the brain, MCs interact with neurons causing neuronal excitation with the production of neuropeptides and the release of inflammatory mediators such as cytokines and chemokines. This article explores the current understanding of MC activation by neuropeptide substance P (SP), corticotropin-releasing hormone (CRH), and neurotensin, and the role of pro-inflammatory cytokines, suggesting a therapeutic effect of the anti-inflammatory cytokines IL-37 and IL-38.

Pleiotrophin attenuates the senescence of dental pulp stem cells.

OBJECTIVES: Pleiotrophin (PTN), a secreted extracellular matrix-associated protein, plays an important role in regulating the osteo/dentinogenic differentiation potential of dental pulp stem cells (DPSCs). Our previous study has demonstrated that PTN expression in young DPSCs was is 10-fold higher than that in aged DPSCs. However, the role of PTN on the in maintaining the stemness of senescent DPSCs remains unclear. The present study aimed to investigate the effect of PTN on senescent DPSCs in vitro. MATERIALS AND METHODS: Dental pulp stem cells were isolated from human third molars. PTN was knocked down using short hairpin RNAs to study the role of PTN on the senescence of DPSCs. DPSCs with aging performance were obtained by a replicative senescence cell model was obtained by the long-term culture of DPSCs to the 15th passage in vitro (P15). We then investigated the effect of PTN on senescent DPSCs (P15 DPSCs). Real-time RT-PCR, western blotting, alizarin red staining, quantitative calcium analysis, SA-ß-Gal staining, CFSE, and cell-counting kit-8 (CCK8) assays were used to study cellular senescence and function. RESULTS: The depletion of PTN increased the ratio of SA-ß-gal-positive cells, upregulated the expression of p16, and down-regulated the expression of TERT and p-p38. Furthermore, 50 pg/ml of PTN recombinant protein rescued these changes the altered ratio of SA-ß-gal-positive cells, decreased the expression of p16, enhanced TERT and p-p38 expression, as well as telomere activity, caused by PTN depletion and long-term culture. The15th passage cells displayed typical aging characteristic, including high ratio of SA-ß-gal-positive cells, increased aging-related gene expression, decreased proliferation rate, high level of Cyclin D expression, and impaired osteo/dentinogenic differentiation potential. However, 50 pg/ml of PTN recombinant protein could partially reverse these alteration rescue these changes. CONCLUSIONS: The present study demonstrated that PTN could protect DPSCs from senescence by improving the proliferation and osteo/dentinogenic differentiation ability, probably through the p38 MAPK pathway.

GM-CSF: A Double-Edged Sword in Cancer Immunotherapy.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that drives the generation of myeloid cell subsets including neutrophils, monocytes, macrophages, and dendritic cells in response to stress, infections, and cancers. By modulating the functions of innate immune cells that serve as a bridge to activate adaptive immune responses, GM-CSF globally impacts host immune surveillance under pathologic conditions. As with other soluble mediators of immunity, too much or too little GM-CSF has been found to promote cancer aggressiveness. While too little GM-CSF prevents the appropriate production of innate immune cells and subsequent activation of adaptive anti-cancer immune responses, too much of GM-CSF can exhaust immune cells and promote cancer growth. The consequences of GM-CSF signaling in cancer progression are a function of the levels of GM-CSF, the cancer type, and the tumor microenvironment. In this review, we first discuss the secretion of GM-CSF, signaling downstream of the GM-CSF receptor, and GM-CSF's role in modulating myeloid cell homeostasis. We then outline GM-CSF's anti-tumorigenic and pro-tumorigenic effects both on the malignant cells and on the non-malignant immune and other cells in the tumor microenvironment. We provide examples of current clinical and preclinical strategies that harness GM-CSF's anti-cancer potential while minimizing its deleterious effects. We describe the challenges in achieving the Goldilocks effect during administration of GM-CSF-based therapies to patients with cancer. Finally, we provide insights into how technologies that map the immune microenvironment spatially and temporally may be leveraged to intelligently harness GM-CSF for treatment of malignancies.

Exploring the management approaches of cytokines including viral infection and neuroinflammation for neurological disorders.

Considerable evidence supports that cytokines are important mediators of pathophysiologic processes within the central nervous system (CNS). Numerous studies have documented the increased production of various cytokines in the human CNS in various neurological and neuropsychiatric disorders. Deciphering cytokine actions in the intact CNS has important implications for our understanding of the pathogenesis and treatment of these disorders. The purpose of this study is to discuss the recent research on treating cytokine storm and amyloids, including stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's condition, Multi-sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS). Neuroinflammation observed in neurological disorders has a pivotal role in exacerbating Aß burden and tau hyperphosphorylation, suggesting that stimulating cytokines in response to an undesirable external response could be a checkpoint for treating neurological disorders. Furthermore, the pro-inflammatory cytokines help our immune system through a neuroprotective mechanism in clearing viral infection by recruiting mononuclear cells. This study reveals that cytokine applications may play a vital role in providing novel regulation and methods for the therapeutic approach to neurological disorders and the causes of the deregulation, which is responsible for neuroinflammation and viral infection. However, it needs to be further investigated to clarify better the mechanisms of cytokine release in response to various stimuli, which could be the central point for treating neurological disorders.

[Pathogenèse de l'infection par le SARS-CoV-2]. / Infection with SARS-CoV-2 : a viral or inflammatory disease ?

PATHOGENESIS OF SARS-COV-2 INFECTION COVID-19 follows a rather stereotyped and reproducible course. While the first events are mediated by direct viral toxicity, resolution of the infection relies on a finely tuned immune response. In patients with severe forms, defects of the initial immune response have been reported, including insufficient type 1 interferon production or signaling, attenuated or skewed adaptative immune response, sometimes due to viral immune escape properties. These defects induce an hyperinflammatory state featuring hypersecretion of pro-inflammatory cytokines, excessive recruitment of immune cells in the lungs and parenchymal lesions, responsible for COVID-19 acute respiratory distress syndrome. Thus, COVID-19 is successively a viral and an inflammatory disease. Clarifying the chronology of these viral and immunological mechanisms allows us to identify a therapeutic logic, which sometimes involves contradictory treatments.

PATHOGENÈSE DE L'INFECTION PAR LE SARS-COV-2 L'infection par le SARS-CoV-2 suit une évolution relativement reproductible qu'il est possible de séparer en plusieurs étapes. Si les premières phases de la maladie sont le siège de cytotoxicité virale, les phases évolutives les plus tardives sont essentiellement la conséquence d'une réponse inflammatoire disproportionnée. Toxicité virale et hyperinflammation sont toutefois intimement liées. Les mécanismes d'évasion virale, l'affaiblissement de la réponse interféron et de la réponse immunitaire adaptative concourent à l'hypersécrétion des cytokines inflammatoires. L'infiltration exagérée des poumons par les macrophages, les neutrophiles et les lymphocytes surpasse les mécanismes de réparation tissulaire et conduit au syndrome de détresse respiratoire aiguë. L'infection par le SARS-CoV-2 est donc successivement une maladie virale puis une maladie inflammatoire. Préciser la chronologie de ces mécanismes viraux et immunologiques permet d'en dégager une logique thérapeutique, qui fait intervenir des traitements parfois contradictoires.

Regenerative medicine for neuropathic pain: physiology, ultrasound and therapies with a focus on alpha-2-macroglobulin.

The currently available drugs to treat neuropathic pain do not provide adequate pain management. As such, other treatments including stem cells, platelet-rich plasma and plasma-derived molecules such as alpha-2 macroglobulin (A2M) are being explored because they show promising potential for neuropathic pain. The various mechanisms and immunomodulatory effects could be a desirable approach in targeting neuropathic pain. This review indicates that A2M can be highly efficacious due to its conformational change during activation and specificity of action on various cytokines. Its ability to reduce neuropathic pain can further the future of neuropathic intervention. However, there is a lack of robust clinical studies and thus further research is needed to verify and expand the understanding of its therapeutic effects.

The currently available drugs to treat neuropathic pain do not provide adequate pain control. As such, other various regenerative treatments modalities are being explored because they show promising potential for neuropathic pain. The various mechanisms and immunity-focused effects could be a desirable approach in targeting neuropathic pain. This review indicates that alpha-2 macroglobulin, a specific plasma derived molecule, can be highly effective due to its shape change during activation and highly specific action on various proteins. Its ability to reduce neuropathic pain can further the future of neuropathic intervention. However, there is a lack of robust clinical studies and thus further research is needed to verify and expand the understanding of its therapeutic effects.

The emerging role of the neuroimmune cytokine interleukin-31 in chronic inflammatory skin diseases.

Chronic inflammatory skin diseases pose significant challenges for both patients and clinicians worldwide. Atopic dermatitis (AD), the most common of these diseases, affects up to 8% of the adult population depending on geographic location and demographic group, while prurigo nodularis (PN) is a less common disease that causes significant burden. In these inflammatory skin conditions, pruritus is a cardinal symptom. Interleukin 31 (IL-31), described as a neuroimmune modulator, has been shown to have a prominent role in both inflammation and itch. IL-31 acts through a receptor complex consisting of IL-31 receptor α (IL-31RA) and oncostatin M receptor ß (OSMRß). IL-31 is produced by a variety of cells, including type 2 helper T cells, and IL-31 signaling can activate three important pathways: JAK/STAT, P13K/AKT, and ERK/MAPK. IL-31 is elevated in AD and PN, and is thought to induce chemokine genes CCL1, CCL17, and CCL22. The chemokines recruit T cells to affected skin, where more IL-31 is secreted. The IL-31 receptor complex is also abundant in dorsal root ganglia in human tissue, home of primary sensory neurons and the distal source of "itch sensations." IL-31 and its receptor complex have an important role in chronic inflammatory diseases, including AD and PN, and blocking the IL-31/IL-31RA signaling may represent an important new therapeutic approach for these diseases, which continue to have significant unmet medical needs.

Interleukin-1 Receptor-Like 2: One Receptor, Three Agonists, and Many Implications.

The interleukin (IL)-1 superfamily of cytokines comprises 11 pro- and anti-inflammatory cytokines, which play essential roles during the immune response. Several pathogenic pathways are initiated by IL-1RL2 (interleukin 1 receptor-like 2) signaling, also known as IL-36R, in the skin, lungs, and gut. IL-36 cytokines promote the secretion of proinflammatory cytokines and chemokines, upregulation of antimicrobial peptides, proliferation mediators, and adhesion molecules on endothelial cells. In addition, the IL-36-IL-1RL2 axis has an essential role against viral infections, including a potential role in COVID-19 pathology. The evidence presented in this review highlights the importance of the axis IL-36-IL-1RL2 in the development of several inflammation-related diseases and the healing process. It suggests that IL-1RL2 ligands have specific roles depending on the tissue or cell source. However, there is still much to discover about this cytokine family, their functions in other organs, and how they accomplish a dual effect in inflammation and healing.

Role of immune mediators in predicting hospitalization of SARS-CoV-2 positive patients.

BACKGROUND: Several immune mediators (IM) including cytokines, chemokines, and their receptors have been suggested to play a role in COVID-19 pathophysiology and severity. AIM: To determine if early IM profiles are predictive of clinical outcome and which of the IMs tested possess the most clinical utility. METHODS: A custom bead-based multiplex assay was used to measure IM concentrations in a cohort of SARS-CoV-2 PCR positive patients (n = 326) with varying disease severities as determined by hospitalization status, length of hospital stay, and survival. Patient groups were compared, and clinical utility was assessed. Correlation plots were constructed to determine if significant relationships exist between the IMs in the setting of COVID-19. RESULTS: In PCR positive SARS-CoV-2 patients, IL-6 was the best predictor of the need for hospitalization and length of stay. Additionally, MCP-1 and sIL-2Rα were moderate predictors of the need for hospitalization. Hospitalized PCR positive SARS-CoV-2 patients displayed a notable correlation between sIL-2Rα and IL-18 (Spearman's ρ = 0.48, P=<0.0001). CONCLUSIONS: IM profiles between non-hospitalized and hospitalized patients were distinct. IL-6 was the best predictor of COVID-19 severity among all the IMs tested.

The effect of BKV reactivation on cytokines behavior in kidney transplanted patients.

BACKGROUND: BK virus associated nephropathy (BKVAN) is one of the common causes of graft loss among kidney transplanted recipients (KTRs). The current treatment for BKV nephropathy is decreasing the immunosuppressive regimen in KTRs. Interleukin-27 (IL-27) is a multifunctional cytokine that might be the front-runner of an important pathway in this regard. Therefore, in current study it is tried to evaluate the changes in the expression level of IL-27 and some related molecules, resulting from BKV reactivation in KTR patients. METHODS: EDTA-treated blood samples were collected from all participants. Patients were divided into two groups, 31 kidney transplant recipients with active and 32 inactive BKV infection, after being monitored by Real time PCR (Taq-Man) in plasma. Total of 30 normal individuals were considered as healthy control group. Real time PCR (SYBR Green) technique is used to determine the expression level of studied genes. RESULTS: The results of gene expression comparisons showed that the expression level of IL-27, IFN-γ, TNF-α, TNFR2 and IRF7 genes was significantly higher in inactive group in comparison to active group. The expression level of TLR4 was lower in both active and inactive groups in comparison to control group. ROC curve analysis showed that IL-27 and IRF7 are significantly different amongst other studied genes. Finally, the analyses revealed that the expression level of most of the studied genes (except for TNF-α and TLR4) have significant correlation with viral load. CONCLUSIONS: Our findings revealed that IL-27, IFN-γ, TNF-α, TNFR2 and IRF7 expression level is higher in inactive group and TLR4 expression level is lower in patients' groups in comparison to control group. Also, ROC curve analysis showed IL-27 and IRF7 can significantly differentiate studied groups (BKV active vs. inactive). Therefore, these results might help elucidating the pattern in charge of BKV reactivation in kidney transplanted patients.

Dysregulated B cell function and disease pathogenesis in systemic sclerosis.

Systemic sclerosis (SSc) is a complex, immune-mediated rheumatic disease characterised by excessive extracellular matrix deposition in the skin and internal organs. B cell infiltration into lesional sites such as the alveolar interstitium and small blood vessels, alongside the production of defined clinically relevant autoantibodies indicates that B cells play a fundamental role in the pathogenesis and development of SSc. This is supported by B cell and fibroblast coculture experiments revealing that B cells directly enhance collagen and extracellular matrix synthesis in fibroblasts. In addition, B cells from SSc patients produce large amounts of profibrotic cytokines such as IL-6 and TGF-ß, which interact with other immune and endothelial cells, promoting the profibrotic loop. Furthermore, total B cell counts are increased in SSc patients compared with healthy donors and specific differences can be found in the content of naïve, memory, transitional and regulatory B cell compartments. B cells from SSc patients also show differential expression of activation markers such as CD19 which may shape interactions with other immune mediators such as T follicular helper cells and dendritic cells. The key role of B cells in SSc is further supported by the therapeutic benefit of B cell depletion with rituximab in some patients. It is notable also that B cell signaling is impaired in SSc patients, and this could underpin the failure to induce tolerance in B cells as has been shown in murine models of scleroderma.

The role and function of CD4+ T cells in hepatic ischemia-reperfusion injury.

INTRODUCTION: Hepatic ischemia-reperfusion injury (IRI) is a severe complication frequently encountered in liver surgery, seriously affecting the therapeutic effects, tissue function. Various immune cells are involved in hepatic IRI, including macrophages, NKT cells, DCs, CD4 + T cells, and CD8 + T cells, among which CD4 + T cells play a critical role in this process. This article aims to summarize the functions and changes in various CD4 + T cell type counts and related cytokine levels in hepatic IRI and to review the possible mechanisms of mutual conversion between T cell types. AREAS COVERED: We have covered the functions and changes that occur in Th1, Th17, and Treg cells in liver IRI, as well as the pathways and factors associated with them. We also discuss the prospects of clinical application and future directions for therapeutic advances. EXPERT OPINION: This section explores the current clinical trials involving CD4 + T cells, especially Tregs, explains the limitations of their application, and summarizes the future development trends of cell engineering and their combination with the CAT technology. We also provide new ideas and therapeutic targets for alleviating liver IRI or other liver inflammatory diseases.

The interplay of immunology and cachexia in infection and cancer.

Diverse inflammatory diseases, infections and malignancies are associated with wasting syndromes. In many of these conditions, the standards for diagnosis and treatment are lacking due to our limited understanding of the causative molecular mechanisms. Here, we discuss the complex immunological context of cachexia, a systemic catabolic syndrome that depletes both fat and muscle mass with profound consequences for patient prognosis. We highlight the main cytokine and immune cell-driven pathways that have been linked to weight loss and tissue wasting in the context of cancer-associated and infection-associated cachexia. Moreover, we discuss the potential immunometabolic consequences of cachexia on the basis of newly identified pathways and explore the multilayered area of immunometabolic crosstalk both upstream and downstream of tissue catabolism. Collectively, this Review highlights the intricate relationship of the immune system with cachexia in the context of malignant and infectious diseases.

La inflamación como el nexo entre la enfermedad periodontal y la enfermedad cardiovascular / Inflammation as a link between periodontal disease and cardiovascular disease

La periodontitis es una enfermedad no transmisible, con una alta prevalencia, que oscila entre el 45% y el 50% de la población mundial, ocupando el sexto lugar entre las enfermedades más frecuentes de la huma-nidad. Existe suficiente evidencia que avala la relación entre la enfermedad periodontal y la enfermedad car-diovascular, responsable de aproximadamente el 45% de las muertes en países desarrollados, compren-diendo en su causalidad al infarto de miocardio, el accidente cerebrovascular, la insuficiencia cardíaca y las arritmias, que causan alrededor del 95 % de las muertes relacionadas con la enfermedad cardiovas-cular. Ambas patologías presentan factores de riesgo comunes ampliamente reconocidos, como la diabetes y el tabaquismo, pero además manifiestan caracte-rísticas genéticas y epigenéticas que avalan distintos mecanismos etiopatológicos. Más allá de los factores de riesgo comunes, se han propuesto dos mecanis-mos para explicar la relación entre la enfermedad periodontal y las cardiovasculares. Uno de ellos, constituye la invasión directa de patógenos periodontales en las células endoteliales. El otro mecanismo sugerido (vía indirecta), ocasionado por la respuesta inflamatoria sistémica que resulta en niveles cróni-camente elevados de diferentes citoquinas, también relacionadas con la enfermedad vascular aterosclerotica como IL-1ß, IL-6, IL-8, TNF-α, PCR y la proteína quimioatrayente de monocitos, podría estar mediado por productos bacterianos, como los lipopolisacári-dos que alcanzarían la circulación induciendo una potente respuesta inmunitaria. Estos mecanismos pueden actuar inflamando las células endoteliales, modulando el metabolismo de los lípidos y aumentan-do el estrés oxidativo, favoreciendo la aterosclerosis, conformando la expresión de un fenotipo arterial in-flamatorio, generando el nexo entre la enfermedad periodontal y las patologías cardiovasculares (AU))

Periodontitis is a non-communicable disease which is highly prevalent worldwide. It was reported to range from 45% to 50% around the world and it was the sixth most prevalent condition of humanity. Consistent body of evidence explains the relationship between periodontal disease and other common systemic conditions such as cardiovascular disease. Periodontitis is likely to cause a 45% of deaths in developed countries, including myocardial infarction, stroke, heart failure and arrhythmias that cause about a 95% of deaths related to cardiovascular disease.Both diseases share many risk factors, such as diabetes and smoking; but also, genetic, and epigenetic characteristics support several etiopathological mechanisms. Beyond the common risk factors, two mechanisms have been proposed to elucidate the relationship between the periodontal disease and cardiovascular diseases. One of them supports the concept that periodontal pathogens are capable of the direct invasion of endothelial cells. The other mechanism suggested (indirect pathway), caused by the disease resulting in chronically elevation of CRP, inflammatory cytokines, the monocyte chemoattractant protein, could be mediated by bacterial products, such as lipopolysaccharides, wich induce a potent immune response and can accelerate endothelial dysfunction. These mechanisms may act by inflaming endothelial cells, modulating lipid metabolism and increasing oxidative stress, favoring atherosclerosis, determining the expression of an inflammatory arterial phenotype, generating the link between periodontal disease and cardiovascular pathologies (AU)

CAR-NK Cells: From Natural Basis to Design for Kill.

Chimeric antigen receptors (CARs) are fusion proteins with an extracellular antigen recognition domain and numerous intracellular signaling domains that have been genetically modified. CAR-engineered T lymphocyte-based therapies have shown great success against blood cancers; however, potential fatal toxicity, such as in cytokine release syndrome, and high costs are some shortcomings that limit the clinical application of CAR-engineered T lymphocytes and remain to overcome. Natural killer (NK) cells are the focal point of current immunological research owing to their receptors that prove to be promising immunotherapeutic candidates for treating cancer. However, to date, manipulation of NK cells to treat malignancies has been moderately successful. Recent progress in the biology of NK cell receptors has greatly transformed our understanding of how NK cells recognize and kill tumor and infected cells. CAR-NK cells may serve as an alternative candidate for retargeting cancer because of their unique recognition mechanisms, powerful cytotoxic effects especially on cancer cells in both CAR-dependent and CAR-independent manners and clinical safety. Moreover, NK cells can serve as an 'off-the-shelf product' because NK cells from allogeneic sources can also be used in immunotherapies owing to their reduced risk of alloreactivity. Although ongoing fundamental research is in the beginning stages, this review provides an overview of recent developments implemented to design CAR constructs to stimulate NK activation and manipulate NK receptors for improving the efficiency of immunotherapy against cancer, summarizes the preclinical and clinical advances of CAR-NK cells against both hematological malignancies and solid tumors and confronts current challenges and obstacles of their applications. In addition, this review provides insights into prospective novel approaches that further enhance the efficiency of CAR-NK therapies and highlights potential questions that require to be addressed in the future.

Basophils as a potential therapeutic target in cancer.

Basophils, which are considered as redundant relatives of mast cells and the rarest granulocytes in peripheral circulation, have been neglected by researchers in the past decades. Previous studies have revealed their vital roles in allergic diseases and parasitic infections. Intriguingly, recent studies even reported that basophils might be associated with cancer development, as activated basophils synthesize and release a variety of cytokines and chemokines in response to cancers. However, it is still subject to debate whether basophils function as tumor-protecting or tumor-promoting components; the answer may depend on the tumor biology and the microenvironment. Herein, we reviewed the role of basophils in cancers, and highlighted some potential and promising therapeutic strategies.