Regulation Of Cytokine Secretion Research Articles

Immunomodulatory Biomaterials: Tailoring Surface Properties to Mitigate Foreign Body Reaction and Enhance Tissue Regeneration.

The immune cells have demonstrated the ability to promote tissue repair by removing debris, breaking down the extracellular matrix, and regulating cytokine secretion profile. If the behavior of immune cells is not well directed, chronic inflammation and foreign body reaction (FBR) will lead to scar formation and loss of biomaterial functionality. The immunologic response toward tissue repair or chronic inflammation after injury and implantation can be modulated by manipulating the surface properties of biomaterials. Tailoring surface properties of biomaterials enables the regulation of immune cell fate such as adhesion, proliferation, recruitment, polarization, and cytokine secretion profile. This review begins with an overview of the role of immune cells in tissue healing and their interactions with biomaterials. It then discusses how the surface properties of biomaterials influence immune cell behavior. The core focus is reviewing surface modification methods to create innovative materials that reduce foreign body reactions and enhance tissue repair and regeneration by modulating immune cell activities. The review concludes with insights into future advancements in surface modification techniques and the associated challenges.

Scalable intracellular delivery via microfluidic vortex shedding enhances the function of chimeric antigen receptor T-cells.

Adoptive chimeric antigen receptor T-cell (CAR-T) therapy is transformative and approved for hematologic malignancies. It is also being developed for the treatment of solid tumors, autoimmune disorders, heart disease, and aging. Despite unprecedented clinical outcomes, CAR-T and other engineered cell therapies face a variety of manufacturing and safety challenges. Traditional methods, such as lentivirus transduction and electroporation, result in random integration or cause significant cellular damage, which can limit the safety and efficacy of engineered cell therapies. We present hydroporation as a gentle and effective alternative for intracellular delivery. Hydroporation resulted in 1.7- to 2-fold higher CAR-T yields compared to electroporation with superior cell viability and recovery. Hydroporated cells exhibited rapid proliferation, robust target cell lysis, and increased pro-inflammatory and regulatory cytokine secretion in addition to improved CAR-T yield by day 5 post-transfection. We demonstrate that scaled-up hydroporation can process 5 × 108 cells in less than 10 s, showcasing the platform as a viable solution for high-yield CAR-T manufacturing with the potential for improved therapeutic outcomes.

Scalable intracellular delivery via microfluidic vortex shedding enhances the function of chimeric antigen receptor T-cells.

Adoptive chimeric antigen receptor T-cell (CAR-T) therapy is transformative and approved for hematologic malignancies. It is also being developed for the treatment of solid tumors, autoimmune disorders, heart disease, and aging. Despite unprecedented clinical outcomes, CAR-T and other engineered cell therapies face a variety of manufacturing and safety challenges. Traditional methods, such as lentivirus transduction and electroporation, result in random integration or cause significant cellular damage, which can limit the safety and efficacy of engineered cell therapies. We present hydroporation as a gentle and effective alternative for intracellular delivery. Hydroporation resulted in 1.7- to 2-fold higher CAR-T yields compared to electroporation with superior cell viability and recovery. Hydroporated cells exhibited rapid proliferation, robust target cell lysis, and increased pro-inflammatory and regulatory cytokine secretion in addition to improved CAR-T yield by day 5 post-transfection. We demonstrate that scaled-up hydroporation can process 5 x 108 cells in less than 10 s, showcasing the platform as a viable solution for high-yield CAR-T manufacturing with the potential for improved therapeutic outcomes.

Design of a targeted dual drug delivery system for boosting the efficacy of photoimmunotherapy against melanoma proliferation and metastasis

IntroductionThe combination of a photosensitizer and indoleamine-2,3 dioxygenase (IDO) inhibitor provides a promising photoimmunotherapy (PIT) strategy for melanoma treatment. A dual drug delivery system offers a potential approach for optimizing the inhibitory effects of PIT on melanoma proliferation and metastasis. ObjectiveTo develop a dual drug delivery system based on PIT and to study its efficacy in inhibiting melanoma proliferation and metastasis. MethodsWe constructed a multifunctional nano-porphyrin material (P18-APBA-HA) using the photosensitizer-purpurin 18 (P18), hyaluronic acid (HA), and 4-(aminomethyl) phenylboronic acid (APBA). The resulting P18-APBA-HA was inserted into a phospholipid membrane and the IDO inhibitor epacadostat (EPA) was loaded into the internal phase to prepare a dual drug delivery system (Lip\\EPA\\P18-APBA-HA). Moreover, we also investigated its physicochemical properties, targeting, anti-tumor immunity, and anti-tumor proliferation and metastasis effects. ResultsThe designed system utilized the pH sensitivity of borate ester to realize an enhanced-targeting strategy to facilitate the drug distribution in tumor lesions and efficient receptor-mediated cellular endocytosis. The intracellular release of EPA from Lip\\EPA\\P18-APBA-HA was triggered by thermal radiation, thereby inhibiting IDO activity in the tumor microenvironment, and promoting activation of the immune response. Intravenous administration of Lip\\EPA\\P18-APBA-HA effectively induced anti-tumor immunity by promoting dendritic cell maturation, cytotoxic T cell activation, and regulatory T cell suppression, and regulating cytokine secretion, to inhibit the proliferation of melanoma and lung metastasis. ConclusionThe proposed nano-drug delivery system holds promise as offers a promising strategy to enhance the inhibitory effects of the combination of EPA and P18 on melanoma proliferation and metastasis.

Positive association between dehydroepiandrosterone (DHEA) and gene expression of the gamma-aminobutyric acid (GABA-A) receptor δ subunit

Gamma-aminobutyric acid A (GABA-A) receptors in the cells of the immune system enhance anti-inflammatory responses by regulating cytokine secretion, cytotoxic responses, and cell activation. In the CNS, the formation of GABA-A subunits into a pentameric structure has been extensively studied; however, no such study has been conducted in the immune system. The objective of the present study was to examine associations between the levels of steroid hormones and GABA-A receptor δ subunit expression in the immune system. We focused on this subunit because GABA-A receptors that contain it become significantly more sensitive to steroid hormones. We collected 80 blood samples from reproductive age women for the purpose of analyzing dehydroepiandrosterone (DHEA), 17β-estradiol, progesterone, and allopregnanolone using liquid chromatography-mass spectrometry (LC-MS). Furthermore, we extracted peripheral blood mononuclear cells (PBMCs) for determining mRNA expression levels of GABA-A receptor genes encoding the δ and ε subunits. We constructed linear mixed effect models for each GABA-A receptor subunit with all 4 steroid hormones, age, and age of menarche as predictors. Whereas DHEA was significantly associated with δ subunit expression (t-value = 2.981; p = 0.003), in line with our hypothesis, none of the steroid hormones were significantly associated with the expression of the ε subunit. Results of this study indicate that significant interactions between hormones from the steroid hormone biosynthesis pathway and GABAergic machinery from the immune cells may be utilized to expand models examining the molecular basis of inflammatory conditions.

Prognostic value of inflammation and immune-related gene NOD2 in clear cell renal cell carcinoma.

Inflammation and immune responses play important roles in cancer development and prognosis. We identified 59 upregulated inflammation- and immune-related genes (IIRGs) in clear cell renal cell carcinoma (ccRCC) from The Cancer Genome Atlas database. Among the upregulated IIRGs, nucleotide binding oligomerization domain 2 (NOD2), PYD and CARD domain (PYCARD) were also confirmed to be upregulated in the Oncomine database and in three independent GEO data sets. Tumor immune infiltration resource database analysis revealed that NOD2 and PYCARD levels were significantly positively correlated with infiltration levels of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages and dendritic cells. Multivariate Cox hazards regression analysis indicated that based on clinical variables (age, gender, tumor grade, pathological TNM stage), NOD2, but not PYCARD, was an independent, unfavorable ccRCC prognostic biomarker. Functional enrichment analyses (GSEA) showed that NOD2 was involved in innate immune responses, inflammatory responses, and regulation of cytokine secretion. Meanwhile, mRNA and protein levels of NOD2 were elevated in four ccRCC cell lines (786-O, ACHN, A498 and Caki-1), and its knockdown significantly inhibited IL-8 secretion, thereby inhibiting ccRCC cell proliferation and invasion. Furthermore, results showed that miR-20b-5p targeted NOD2 to alleviate NOD2-mediated IL-8 secretion. In conclusion, NOD2 is a potential prognostic biomarker for ccRCC and the miR-20b-5p/NOD2/IL-8 axis may regulate inflammation- and immune-mediated tumorigenesis in ccRCC.

Investigation of the In Vitro Immunomodulatory Effects of Extracts from Green-Lipped Mussels (Perna canaliculus)

The immune system plays a crucial role in defending the body against foreign invaders, and the balance of various polyunsaturated fatty acids, such as alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), can impact immune cell functions and overall immune responses. This study aimed to assess the effectiveness of mussel oil extracts in modulating inflammatory responses by analysing their effects on immune cell lines and cytokine expression. Four different mussel oil extracts were obtained using two extraction methods (organic solvent and supercritical CO2 extraction) from two tissue sources (fresh and commercial). These extracts were then tested at various concentrations on T lymphocyte (Jurkat) cells, monocytes, and macrophages (THP-1 and U-937). Cytokine levels were quantified using ELISA. The results showed that the solvent-extracted samples had a dose-dependent effect on tumour necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) cytokine secretion in THP-1 and U937 cells, with the extract from a commercial mussel powder being more efficient than the extract from fresh powder. However, supercritical CO2 samples showed elevated cytokine secretion levels despite their high omega-3 content. Furthermore, 100 ug/mL extract from fresh powder successfully reduced interleukin-2 (IL-2) secretion while maintaining cell viability after stimulation. The study demonstrated that solvent-extracted mussel oil can effectively regulate cytokine secretion, modulate immune cell activation, and alleviate inflammation. These findings offer valuable insights into using mussel oil extracts to treat inflammatory disorders and enhance immune responses.

Abstract A014: Oncogenic PIK3CA on therapeutic resistance and cellular heterogeneity in malignant vascular cancer

Abstract Angiosarcoma is an extremely rare and aggressive cancer that originates from endothelial cells lining blood or lymphatic vessels. The PI3K-AKT pathway plays a crucial role in angiogenesis and pathogenesis of this vascular cancer. Multi-omics studies have identified oncogenic mutations in the PIK3CA, PIK3R1, and PTEN genes involved in the PI3K-AKT pathway in human and canine angiosarcomas. Recently, the FDA approved alpelisib, a PI3K-alpha specific inhibitor, for breast cancer patients with PIK3CA mutations. However, less than 30% of patients treated with alpelisib showed an overall response. Thus, understanding how PIK3CA mutant cells acquire therapeutic resistance is of high importance, yet it remains largely unexplored. In this study, we aimed to determine the molecular effects of PIK3CA mutations on therapeutic resistance against PI3K inhibitors in angiosarcomas. Specifically, PIK3CA H1047R mutations were induced in DHSA-1426 and COSB canine hemangiosarcoma cell lines using CRISPR/Cas9-mediated gene editing, and mutant clones were clonally selected. RNA-seq analysis from the PIK3CA mutant cells and 74 canine hemangiosarcoma tissue samples demonstrated that the activation of the oncogenic PI3K pathway increased cytokine and chemokine secretion, possibly contributing to an immunogenic and inflammatory tumor phenotype. Alpelisib completely abrogated AKT phosphorylation and decreased cytokine and chemokine expression in PIK3CA mutant cells. However, alpelisib showed only moderate potency in inhibiting cell proliferation of the mutant cells, demonstrating partial resistance. Subsequently, our single-cell RNA-seq analysis identified drug-resistant cell clusters within the total cell population. Marker gene analysis revealed that the resistant cell clusters upregulated genes associated with the G protein pathway (GNAI1, VAV3, and GNG11), adenylyl cyclase pathway (PDE4D and PDE7B), calcium signaling pathway (RYR3 and CAMK2D), TGF-beta pathway (TGFB2 and TGFBR2), and the anti-apoptotic gene BCL2. These pathways are all associated with RAS-MAPK signaling, and we confirmed enhanced phosphorylation of ERK upon alpelisib treatment through western blotting. Further, pseudo-time analysis using Monocle 3 indicated that the resistant cell clusters shared a similar differentiation time point with the sensitive cell clusters within the PIK3CA mutant population. Our single-cell trajectory data suggest that therapeutic resistance to alpelisib could be independent of differentiation level. Instead, it may involve an evolutionary program controlled by specific selective pressures between resistant and sensitive cells, potentially associated with immune regulatory mechanisms. Our ongoing work is evaluating whether a cellular autonomous program that regulates cytokine secretion induced by PIK3CA mutation contributes to therapeutic resistance in the tumor microenvironment through in vivo experiment. This study will provide insights into potential mechanisms governing the cellular evolution process of PIK3CA mutant cells, which promote drug resistance. Citation Format: Donghee Lee, Emma Kozurek, Md Abdullah, Rong Li, Joanne Kim, Erin B. Dickerson, Jong Hyuk Kim. Oncogenic PIK3CA on therapeutic resistance and cellular heterogeneity in malignant vascular cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A014.

Research Progress on the Effect and Mechanism of Exercise Intervention on Sarcopenia Obesity.

With the increasingly severe situation of obesity and population aging, there is growing concern about sarcopenia obesity (SO). SO refers to the coexistence of obesity and sarcopenia, which imposes a heavier burden on individuals and society compared to obesity or sarcopenia alone. Therefore, comprehending the pathogenesis of SO and implementing effective clinical interventions are vital for its prevention and treatment. This review uses a comprehensive literature search and analysis of PubMed, Web of Science, and CNKI databases, with search terms including "Sarcopenic obesity", "exercise", "cytokines", "inflammation", "mitochondrial quality control", and "microRNA", covering relevant studies published up to July 2024. The results indicate that the pathogenesis of SO is complex, involving mechanisms like age-related changes in body composition, hormonal alterations, inflammation, mitochondrial dysfunction, and genetic and epigenetic factors. Regarding exercise interventions for SO, aerobic exercise can reduce fat mass, resistance exercise can increase skeletal muscle mass and strength, and combined exercise can achieve both, making it the optimal intervention for SO. The potential mechanisms by which exercise may prevent and treat SO include regulating cytokine secretion, inhibiting inflammatory pathways, improving mitochondrial quality, and mediating microRNA expression. This review emphasizes the effectiveness of exercise interventions in mitigating sarcopenic obesity through comprehensive analysis of its multifactorial pathogenesis and the mechanistic insights into exercise's therapeutic effects. Understanding these mechanisms informs targeted therapeutic strategies aimed at alleviating the societal and individual burdens associated with SO.

Exploring the In Vitro Protective Effects of Green-Lipped Mussel (GLM) Oil Extract against Biomarkers of Glucose Metabolism and Inflammation in Chondrocyte Cells

Chondrocyte behavior is critical in osteoarthritis (OA) progression and cartilage deterioration. Recent studies have shown that green-lipped mussel (GLM) oil extracts obtained through solvent extraction can regulate cytokine secretion in cell lines, potentially reducing inflammation and immune cell activation. This study investigates the effects of these extracts on human chondrocyte cell lines to understand their impact on osteoarthritis development. Chondrocyte cultures exposed to osteoarthritis-related inflammatory factors were treated with various concentrations of GLM oil. The results revealed that mussel oils, particularly a commercial mussel powder extract (SOLV.COM), enhance glucose uptake and protect chondrocyte cells. SOLV.COM effectively manages the release of inflammatory markers like interleukin-6 (IL-6) and matrix metalloproteinases-3 (MMP-3), showing increased deoxyglucose uptake. This study highlights the significant influence of extract choice on managing interleukin-6 (IL-6) secretion and cellular activation pathways, demonstrating the potential of SOLV.COM in managing osteoarthritis by controlling reactive oxygen production, regulating glucose metabolism, and inflammatory markers.

Synaptotagmin-11 regulates immune functions of microglia invivo.

Membrane trafficking pathways mediate key microglial activities such as cell migration, cytokine secretion, and phagocytosis. However, the underlying molecular mechanism remains poorly understood. Previously, we found that synaptotagmin-11 (Syt11), a non-Ca2+ -binding Syt associated with Parkinson's disease (PD) and schizophrenia, inhibits cytokine release and phagocytosis in primary microglia. Here we reported the invivo function of Syt11 in microglial immune responses using an inducible microglia-specific Syt11-conditional-knockout (cKO) mouse strain. Syt11-cKO resulted in activation of microglia and elevated mRNA levels of IL-6, TNF-α, IL-1β, and iNOS in various brain regions under both resting state and LPS-induced acute inflammation state in adult mice. In a PD mouse model generated by microinjection of preformed α-synuclein fibrils into the striatum, a reduced number of microglia migrated toward the injection sites and an enhanced phagocytosis of α-synuclein fibrils by microglia were found in Syt11-cKO mice. To understand the molecular mechanism of Syt11 function, we identified its direct binding proteins vps10p-tail-interactor-1a (vti1a) and vti1b. The linker domain of Syt11 interacted with both proteins and a peptide derived from it competitively inhibited the interaction of Syt11 with vti1a/vti1b invitro and in cells. Importantly, application of this peptide induced more cytokine secretion in wild-type microglia upon LPS treatment, phenocopying defects in Syt11 knockdown cells. Altogether, we propose that Syt11 inhibits microglial activation invivo and regulates cytokine secretion through interactions with vti1a and vti1b.

Reduction of SGLT2 protein levels inhibits cortisol secretion through regulation of cytokine secretion

Reduction of SGLT2 protein levels inhibits cortisol secretion through regulation of cytokine secretion

Galectin-9 interacts with Vamp-3 to regulate cytokine secretion in dendritic cells

Intracellular vesicle transport is essential for cellular homeostasis and is partially mediated by SNARE proteins. Endosomal trafficking to the plasma membrane ensures cytokine secretion in dendritic cells (DCs) and the initiation of immune responses. Despite its critical importance, the specific molecular components that regulate DC cytokine secretion are poorly characterised. Galectin-9, a ß-galactoside-binding protein, has emerged as a novel cellular modulator although its exact intracellular roles in regulating (immune) cell homeostasis and vesicle transport are virtually unknown. We investigated galectin-9 function in primary human DCs and report that galectin-9 is essential for intracellular cytokine trafficking to the cell surface. Galectin-9-depleted DCs accumulate cytokine-containing vesicles in the Golgi complex that eventually undergo lysosomal degradation. We observed galectin-9 to molecularly interact with Vamp-3 using immunoprecipitation-mass-spectrometry and identified galectin-9 was required for rerouting Vamp-3-containing endosomes upon DC activation as the underlying mechanism. Overall, this study identifies galectin-9 as a necessary mechanistic component for intracellular trafficking. This may impact our general understanding of vesicle transport and sheds new light into the multiple roles galectins play in governing cell function.Graphical abstract

Paraprobiotics: definition, manufacturing methods, and functionality.

Probiotics are living microorganisms that are beneficial to the host, enhancing the immune response by promoting antibody production, regulating cytokine secretion, and stimulating T cells. However, probiotics have limitations in that they require viability control and have a short shelf life. Recently, the use of paraprobiotics has gained attention. These include dead bacterial cells, bacterial fractions, and cell lysate that have health benefits and are stable and safe for use. Paraprobiotics comprise molecules of bacterial cell wall compounds, such as peptidoglycans, teichoic acids, polysaccharides, and cell surface proteins. Paraprobiotics are manufactured by a diverse range of techniques, including thermal treatments, high pressure, ultraviolet rays, sonication, ionizing radiation, and pH modification. Their beneficial health effects include immunomodulatory, intestinal balancing, anticancer, and antimicrobial activities. Therefore, this review summarizes and discusses the manufacturing methods and bioavailability of paraprobiotics and suggests their potential health advantages.

Selenoprotein S Interacts with the Replication and Transcription Complex of SARS-CoV-2 by Binding nsp7

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) replicates and evades detection using ER membranes and their associated protein machinery. Among these hijacked human proteins is selenoprotein S (selenos). This selenoprotein takes part in the protein quality control, signaling, and the regulation of cytokine secretion. While the role of selenos in the viral life cycle is not yet known, it has been reported to interact with SARS-CoV-2 nonstructural protein 7 (nsp7), a viral protein essential for the replication of the virus. We set to study whether selenos and nsp7 interact directly and if they can still bind when nsp7 is bound to the replication and transcription complex of the virus. Using biochemical assays, we show that selenos binds directly to nsp7. In addition, we found that selenos can bind to nsp7 when it is in a complex with the coronavirus's minimal replication and transcription complex, comprised of nsp7, nsp8, and the RNA-dependent RNA polymerase nsp12. In addition, through crosslinking experiments, we mapped the interaction sites of selenos and nsp7 in the replication complex and showed that the hydrophobic segment of selenos is essential for binding to nsp7. This arrangement leaves an extended helix and the intrinsically disordered segment of selenos—including the reactive selenocysteine—exposed and free to potentially recruit additional proteins to the replication and transcription complex.

Metabolic Reprogramming of NK Cells by Black Phosphorus Quantum Dots Potentiates Cancer Immunotherapy.

Low persistence, metabolic dysfunction in microenvironment, and tumor-derived immunosuppression of Natural killer (NK) cells in patients are greatly limited the successful clinical application of NK cell-based cancer immunotherapy. Interestingly, herein that human serum albumin-encapsulated black phosphorus quantum dots (BPQDs@HSA) can effectively augment antitumor efficacy of clinical patients-derived NK cell immunotherapy is found. As the donor of phosphate group, BPQDs@HSA binds with the protein of phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1A) and activates the downstream PI3K-Akt and mTOR signaling pathways to reprogram cell metabolism of glycolysis and further promote the oxidative phosphorylation, sequentially maintains the cell viability and immunity of NK cells. And multiomics analysis is therefore conducted to reveal the underlying immunoregulation mechanisms, and that BPQDs@HSA can interact with the Toll-like receptor (TLR) on the NK cell surface and increase the expression level of mTOR, and thus activate downstream NF-κB signalling pathways to regulate cytokine secretion and enhance immune tumoricidal is found. BPQDs@HSA can also enhance immune surveillance, relieve immune suppression, and inhibit tumor immune escape. Collectively, this study not only demonstrates a successful strategy for nanomedicine-potentiated immune-cancer therapy, but also sheds light on the understanding of interface between nanomedicine and immune cells activation.

Tumor-associated macrophages in tumor progression and the role of traditional Chinese medicine in regulating TAMs to enhance antitumor effects.

PurposeTo emphasize the importance of tumor-associated macrophages (TAMs) in tumor immunity and to describe the ways in which extracts from Traditional Chinese Medicine (TCM) achieve tumor therapy by modulating macrophages.SignificanceBy summarizing these available data, this review focused on TAMs and TCM and can build the foundation for future research on antitumor therapeutics.MethodsIn this review, we summarized the key functions of TAMs in cancer development and overviewed literature on TCM targeting TAMs together with other immune cells aiming to enhance antitumor immunity.ConclusionsWith an indispensable role in antitumor immunity, TAMs contribute to tumor progression, migration, invasion, angiogenesis, lymphangiogenesis, and immunosuppressive microenvironment. In recent years, TCM has gradually gained attention as a potential antitumor adjunctive therapy in preclinical and clinical trials. TCM is also a regulator of cytokine secretion and cell surface molecule expression in balancing the tumor microenvironment (TME), especially macrophage activation and polarization. Therefore, it is believed that TCM could serve as modifiers with immunomodulatory capability.

Immunomodulatory Effects of Probiotics on COVID-19 Infection by Targeting the Gut-Lung Axis Microbial Cross-Talk.

The ecosystem of the human gastrointestinal tract, named gut microbiota, represents the most thoroughly mapped ecosystem. Perturbations on bacterial populations cause dysbiosis, a condition correlated to a wide range of autoimmune, neurological, metabolic, cardiovascular, and respiratory diseases. The lungs have their flora, which are directly related to the gut flora via bidirectional communication allowing the transport of microbial metabolites and toxins produced by intestinal bacteria through the circulation and lymphatic system. This mutual microbial cross-talk communication called the gut–lung axis modulates the immune and inflammatory response to infections. COVID-19 causes dysbiosis, altered intestinal permeability, and bacterial translocation. Dysbiosis, through the gut–lung axis, promotes hyper-inflammation, exacerbates lung damage, and worsens clinical outcomes. Preclinical and clinical studies have shown that probiotics can regulate cytokine secretion, thus affecting both nonspecific and specific immunity. Probiotics act by blocking the virus from invading and proliferating in host cells, by stimulating the immune response, and by suppressing the activation of NLRP3 inflammasome. Herein, we reviewed the evidence from preclinical and clinical studies evaluating the effect of probiotics administration on the immune response to COVID-19 infection by targeting the gut–lung axis microbial cross-talk.

Autophagy-Mediated Inflammatory Cytokine Secretion in Sporadic ALS Patient iPSC-Derived Astrocytes.

Background Astrocytes can be involved in motor neuron toxicity in amyotrophic lateral sclerosis (ALS) induced by noncell autonomous effects, and inflammatory cytokines may play the main role in mediating this process. However, the etiology of aberrant cytokine secretion is unclear. The present study assessed possible involvement of the mTOR-autophagy pathway in aberrant cytokine secretion by ALS patient iPSC-derived astrocytes. Method and Results. PBMCs from sporadic ALS patients and control subjects were reprogrammed into iPSCs, which were then differentiated into astrocytes and/or motor neurons. Comparison with control astrocytes indicated that conditioned medium of ALS astrocytes reduced the viability of the control motor neurons (p < 0.05) assessed using the MTT assay. The results of ELISA showed that the concentrations of TNFα, IL1β, and IL6 in cell culture medium of ALS astrocytes were increased (p < 0.05). ALS astrocytes had higher p62 and mTOR levels and lower LC3BII/LC3BI ratio and ULK1 and p-Beclin-1 (Ser15) levels (p < 0.05), indicating defective autophagy. Exogenous inhibition of the mTOR-autophagy pathway, but not the activation of the pathway in control subject astrocytes, increased the levels of p62 and mTOR and concentration of IL-1β, TNF-α, and IL-6 in cell culture medium and decreased the LC3BII/LC3BI ratio and levels of ULK1 and p-Beclin-1 (Ser15), and these changes were comparable to those in ALS astrocytes. After 48 h of rapamycin (autophagy activator) and 3-methyladenine (autophagy inhibitor) treatments, the exogenous activation of the mTOR-autophagy pathway, but not inhibition of the pathway, in ALS astrocytes significantly reduced the concentrations of TNFα, IL1β, and IL6 in cell culture medium and reduced the levels of p62, while increasing the levels of LC3B-II/LC3B-I, ULK1, and p-Beclin-1 (Ser15), and these changes were comparable to those in control subject astrocytes. Conclusion Alteration in the mTOR/ULK1/Beclin-1 pathway regulated cytokine secretion in ALS astrocytes, which was able to lead to noncell autonomous toxicity. Autophagy activation mitigated cytokine secretion by ALS astrocytes.

Participation of MAPK and PI3K in Regulation of Cytokine Secretion by Peripheral Blood Monocular Cells in Response to Escherichia coli LPS and rDer p 2 Combination.

Search for the effective approaches to treat acute inflammation caused by combination of allergens and infectious agents is an important task for public health worldwide. House dust mites Dermatophagoides pteronyssinus are the source of allergens of the Der p groups and of microbial compounds, in particular, lipopolysaccharides (LPS). LPS and Der p 2 induce secretion of pro-inflammatory cytokines via activation of kinases p38 MAPK, MEK1/2, and PI3K. Participation of these kinases in the regulation of cells response to combined exposure to LPS and Der p 2 has not been sufficiently studied. We studied the effects of kinases (p38 MAPK, MEK1/2, and PI3K) inhibition on secretion of cytokines (TNF, IL-8, and IL-6) by peripheral blood mononuclear cells (PBMC) of healthy volunteers in response to E. coli LPS and rDer p 2. Contribution of kinases to the regulation of cell response to different agents (rDer p 2 and/or LPS) was revealed. It was found that p38 MAPK plays a key role in the regulation of secretion TNF by PBMC in response to the combination of LPS and rDer p 2. MEK1/2-dependent signaling is the main pathway for the synthesis of TNF and IL-8 in response to LPS and rDer p 2. PI3K-dependent signaling negatively regulates TNF production during rDer p 2-induced cell activation, but is not involved in the response to the combination of LPS and rDer p 2. PI3K-dependent signaling in the regulation of PBMC cytokine synthesis is most pronounced in response to their activation by rDer p 2. Understanding the mechanisms of immune cell responses to combinations of inflammatory agents could facilitate the search for new intracellular targets for anti-inflammatory therapy.