Mature Cells Research Articles

Loss of ARID3A perturbs intestinal epithelial proliferation-differentiation ratio and regeneration.

Intestinal stem cells at the crypt divide and give rise to progenitor cells that proliferate and differentiate into various mature cell types in the transit-amplifying (TA) zone. Here, we showed that the transcription factor ARID3A regulates intestinal epithelial cell proliferation and differentiation at the TA progenitors. ARID3A forms an expression gradient from the villus tip to the upper crypt mediated by TGF-β and WNT. Intestinal-specific deletion of Arid3a reduces crypt proliferation, predominantly in TA cells. Bulk and single-cell transcriptomic analysis shows increased enterocyte and reduced secretory differentiation in the Arid3a cKO intestine, accompanied by enriched upper-villus gene signatures of both cell lineages. We find that the enhanced epithelial differentiation in the Arid3a-deficient intestine is caused by increased binding and transcription of HNF1 and HNF4. Finally, we show that loss of Arid3a impairs irradiation-induced regeneration with sustained cell death and reprogramming. Our findings imply that Arid3a functions to fine-tune the proliferation-differentiation dynamics at the TA progenitors, which are essential for injury-induced regeneration.

Pseudo-3D Topological Alignments Regulate Mechanotransduction and Maturation of Smooth Muscle Cells.

Smooth muscle cells (SMCs) sense and respond to mechanical stimuli in their extracellular microenvironments (ECMs), playing a crucial role in muscle tissue engineering. Increasing evidence from topological cues-mediated mechanotransduction of SMCs in ECMs has suggested some potential underlying mechanisms of how SMC functions and maturation are regulated by their mechanosensing leading to transduction. However, how the expression of yes-associated protein 1 (YAP) influences the phenotypic shift from synthetic to contractile is still controversial. Here, pseudo-3D topological alignments mimicking native muscle tissues are generated using laser-cutter engraving to explore the influence of topological cues on SMC mechanotransduction and maturation. The analysis of topological cue-mediated mechanotransduction and maturation marker expression revealed YAP is involved in mechanotransduction for SMCs cultured on cross-patterned substrates in the presence of cell-cell interactions. Moreover, these SMCs with YAP-linked mechanosensing showed higher expression of calponin, indicating a shift toward contractile phenotypes in vitro and in vivo. Furthermore, it showed skeletal muscle cells has different mechanosensing and maturation mechanisms compared to SMCs, revealing muscle type-dependent different sensing of topological cues, and converting into maturation-associated signaling cascades. This study provides insights into the regulation of SMC mechanotransduction and maturation by topological cues, suggesting the involvement of YAP-linked signaling pathways in this process.

CD28 Costimulation Augments CAR Signaling in NK Cells via the LCK/CD3ζ/ZAP70 Signaling Axis.

Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity, using a CD70-targeting CAR. We found that CD28, a costimulatory molecule not inherently present in mature NK cells, significantly enhanced the antitumor efficacy and long-term cytotoxicity of CAR-NK cells both in vitro and in multiple xenograft models of hematologic and solid tumors. Mechanistically, we showed that CD28 linked to CD3ζ creates a platform that recruits critical kinases, such as lymphocyte-specific protein tyrosine kinase (LCK) and zeta-chain-associated protein kinase 70 (ZAP70), initiating a signaling cascade that enhances CAR-NK cell function. Our study provides insights into how CD28 costimulation enhances CAR-NK cell function and supports its incorporation in NK-based CARs for cancer immunotherapy. Significance: We demonstrated that incorporation of the T-cell-centric costimulatory molecule CD28, which is normally absent in mature natural killer (NK) cells, into the chimeric antigen receptor (CAR) construct recruits key kinases including lymphocyte-specific protein tyrosine kinase and zeta-chain-associated protein kinase 70 and results in enhanced CAR-NK cell persistence and sustained antitumor cytotoxicity.

Chimeric antigen receptor-T-cell therapies going viral: latent and incidental viral infections.

Infections are the leading cause of non-relapse mortality following chimeric antigen receptor (CAR)-T-cell therapy, with viral infections being frequent both in the early and late phases post-infusion. We review the epidemiology of viral infections and discuss critical approaches to prevention and management strategies in this setting. Herpesviruses dominate the early period. herpes simplex virus and varicella zoster virus infections are rare due to widespread antiviral prophylaxis, but cytomegalovirus (CMV) reactivation is increasingly observed, particularly in high-risk groups including B cell maturation antigen (BCMA)-CAR-T-cell therapy recipients and patients receiving corticosteroids. While CMV end-organ disease is rare, CMV is associated with increased mortality, emphasizing the need to evaluate the broader impact of CMV on long-term hematological, infection, and survival outcomes. Human herpesvirus-6 (HHV-6) has also emerged as a concern, with its diagnosis complicated by overlapping symptoms with neurotoxicity, underscoring the importance of considering viral encephalitis in differential diagnoses. Respiratory viruses are the most common late infections with a higher incidence after BCMA CAR-T-cell therapy. Vaccination remains a critical preventive measure against respiratory viruses but may be less immunogenic following CAR-T-cell therapy. The optimal timing, type of vaccine, and dosing schedule require further investigation. A better understanding of viral epidemiology and preventive trials are needed to improve infection prevention practices and outcomes following CAR-T-cell therapies.

Prolonged Omicron-Specific B Cell Maturation Alleviates Immune Imprinting Induced by SARS-CoV-2 Inactivated Vaccine

SARS-CoV-2 ancestral strain-induced immune imprinting poses great challenges to updating vaccines for new variants. Studies showed that repeated Omicron exposures could override immune imprinting induced by inactivated vaccines but not mRNA vaccines, a disparity yet to be understood. Here, we analyzed the immune imprinting alleviation in inactivated vaccine (CoronaVac) cohorts after a long-term period following breakthrough infections (BTI). We observed in CoronaVac-vaccinated individuals who experienced BA.5/BF.7 BTI, the proportion of Omicron-specific memory B cells (MBCs) substantially increased after an extended period post-Omicron BTI, with their antibodies displaying enhanced somatic hypermutation and neutralizing potency. Consequently, the neutralizing antibody epitope distribution encoded by MBCs post-BA.5/BF.7 BTI after prolonged maturation closely mirrors that in BA.5/BF.7-infected unvaccinated individuals. Together, these results indicate the activation and expansion of Omicron-specific naïve B cells generated by first-time Omicron exposure helped to alleviate CoronaVac-induced immune imprinting, and the absence of this process should have caused the persistent immune imprinting seen in mRNA vaccine recipients.

Transcutaneous Immunization of 1D Rod-Like Tobacco-Mosaic-Virus-Based Peptide Vaccine via Tip-Loaded Dissolving Microneedles.

Peptide vaccines induce specific neutralizing antibodies and are effective in disease prevention and treatment. However, peptide antigens have a low immunogenicity and are unstable, requiring efficient vaccine carriers to enhance their immunogenicity. Here, we develop a tobacco mosaic virus (TMV)-based peptide vaccine for transdermal immunization using a tip-loaded dissolving microneedle (MN) patch. TMV is decorated with the model peptide antigen PEP3. The prepared TMV-PEP3 promotes dendritic cell maturation and induces dendritic cells to overexpress MHC II, costimulatory factors, and pro-inflammatory factors. By encapsulation of TMV-PEP3 in the tips of a trehalose MN, TMV-PEP3 can be delivered by MN and significantly promote local immune cell infiltration. In vivo studies show that both subcutaneous injection and MN administration of TMV-PEP3 increase the production of anti-PEP3 IgG antibodies and the harvested serum can induce complement-dependent cytotoxicity. This work provides a promising strategy for constructing efficient and health-care-friendly peptide vaccines.

Decoupling immunomodulatory properties from lipid binding in the α-pore-forming toxin Sticholysin II

Sticholysin II (StII), a pore-forming toxin from the marine anemone Stichodactyla helianthus, enhances an antigen-specific cytotoxic T lymphocyte (CTL) response when co-encapsulated in liposomes with a model antigen. This capacity does not depend exclusively on its pore-forming activity and is partially supported by its ability to activate Toll-like receptor 4 (TLR4) in dendritic cells, presumably by interacting with this receptor or by triggering signaling cascades upon binding to lipid membrane. In order to investigate whether the lipid binding capacity of StII is required for immunomodulation, we designed a mutant in which the aromatic amino acids from the interfacial binding site Trp110, Tyr111 and Trp114 were substituted by Ala. In the present work, we demonstrated that StII3A keeps the secondary structure composition and global folding of StII, while it loses its lipid binding and permeabilization abilities. Despite this, StII3A upregulates dendritic cells maturation markers, enhances an antigen-specific effector CD8+ T cells response and confers antitumor protection in a preventive scenario in C57BL/6 mice. Our results indicate that a mechanism independent of its lipid binding ability is involved in the immunomodulatory capacity of StII, pointing to StII3A as a promising candidate to improve the reliability of the Sts-based vaccine platform.

Reprogramming the Tumor Immune Microenvironment Through Activatable Photothermal Therapy and GSH depletion Using Liposomal Gold Nanocages to Potentiate Anti-Metastatic Immunotherapy.

Cancer immunotherapy offers significant clinical benefits for patients with advanced or metastatic tumors. However, immunotherapeutic efficacy is often hindered by the tumor microenvironment's high redox levels, leading to variable patient outcomes. Herein, a therapeutic liposomal gold nanocage (MGL) is innovatively developed based on photo-triggered hyperthermia and a releasable strategy by combining a glutathione (GSH) depletion to remodel the tumor immune microenvironment, fostering a more robust anti-tumor immune response. MGL comprises a thermosensitive liposome shell and a gold nanocage core loaded with maleimide. The flexible shell promotes efficient uptake by cancer cells, enabling targeted destruction through photothermal therapy while triggering immunogenic cell death and the maturation of antigen-presenting cells. The photoactivated release of maleimide depletes intracellular GSH, increasing tumor cell sensitivity to oxidative stress and thermal damage. Conversely, GSH reduction also diminishes immunosuppressive cell activity, enhances antigen presentation, and activates T cells. Moreover, photothermal immunotherapy decreases elevated levels of heat shock proteins in tumor cells, further increasing their sensitivity to hyperthermia. In summary, MGL elicited a robust systemic antitumor immune response through GSH depletion, facilitating an effective photothermal immunotherapeutic strategy that reprograms the tumor microenvironment and significantly inhibits primary and metastatic tumors. This approach demonstrates considerable translational potential and clinical applicability.

PAD4 Inhibitor-Loaded Layered Double Hydroxide Nanosheets as a Multifunctional Nanoplatform for Photodynamic Therapy-Mediated Tumor Metastasis Treatment.

Photodynamic therapy (PDT) is demonstrated to be effective in inducing antitumor immune responses for tumor metastasis treatment. However, tumor hypoxia, inferior tissue penetration of light, and low singlet oxygen (1O2) quantum yield significantly hamper the efficacy of PDT, thus weakening its immune function. Moreover, PDT-mediated neutrophil extracellular traps (NETs) formation can further reduce the therapeutic effectiveness. Herein, the use of defect-rich CoMo-layered double hydroxide (DR-CoMo-LDH) nanosheets as a carrier to load a typical peptidyl arginine deiminase 4 inhibitor, i.e., YW4-03, to construct a multifunctional nanoagent (403@DR-LDH) for PDT/immunotherapy, is reported. Specifically, 403@DR-LDH inherits excellent 1O2 generation activity under 1550nm laser irradiation and improves the half-life of YW4-03. Meanwhile, 403@DR-LDH plus 1550nm laser irradiation can stimulate immunogenic cell death to promote the maturation of dendric cells and activation/infiltration of T cells and significantly downregulate H3cit protein expression to inhibit NETs formation, synergistically promoting the antitumor metastasis effect. Taken together, 403@DR-LDH can kill cancer cells and inhibit tumor growth/metastasis under 1550nm laser irradiation. Single-cell analysis indicates that 403@DR-LDH can regulate the ratio of immune cells and immune-related proteins to improve the tumor immune microenvironment, showing strong efficacy to inhibit the tumor growth, metastasis, and recurrence.

B-343 Development of CD40 and HER2 Bispecific Antibodies for Enhanced Efficacy against HER2-Positive Tumors

Abstract Background CD40, a member of the tumor necrosis factor superfamily, is primarily expressed on antigen-presenting cells. This receptor plays a crucial role in facilitating the interaction between dendritic cells, activating antigen-specific T cells. Agonist antibodies targeting the CD40 receptor have the potential to mimic the natural CD40 ligand, fostering dendritic cell maturation and stimulating immunity against “cold” tumors. Although this approach has shown promise in preclinical studies, translating it to clinical success has been challenging. Only modest anti-tumor activity was observed in cancer patients, and none of the developed CD40 monoclonal antibodies (mAbs) progressed beyond early clinical trials, highlighting a need for improved anti-tumor efficacy. Methods In this study, we successfully developed an anti-human CD40 agonist rabbit monoclonal antibody using Yurogen's proprietary SMAB(TM) platform. The most potent CD40 mAb clone was combined with trastuzumab (an anti-HER2 mAb) to create a therapeutic bispecific antibody. Our goal is to leverage immune cell activation through HER2-targeted cancer therapy to achieve enhanced anti-tumor activity. Dozens of diverse CD40xHER2 bispecific antibody designs (both symmetry and asymmetry) were explored, with careful evaluation of expression yield, purity, and binding profiles for each target respectively. Results A few bispecific antibody designs demonstrated robust binding to both HER2 and CD40 antigen proteins, as well as receptor-expressing cell lines. Notably, two developed bispecific antibodies exhibited potent killing of HER2-positive cancer cells with the assistance of innate immune cells. Conclusions In sum, this study provides novel insights into designing bispecific antibodies against HER2 and CD40, offering a promising avenue for advancing cancer immunotherapy.

Helios-Illuminating the way for lymphocyte self-control.

Transcription factor Helios, encoded by the IKZF2 gene, has an important role in regulatory T cells by stabilizing their suppressive phenotype. While Helios is prominently expressed in regulatory T cells, its expression extends beyond to include effector T cells, follicular regulatory T cells, B cells, and innate-like lymphocyte populations. Recent characterizations of patients with inborn error of immunity due to damaging IKZF2 variants coupled with translational research on lymphocytes from healthy individuals, have increased our understanding on Helios' multifaceted role in controlling the human adaptive immune system. A less studied role for Helios beyond the stabilizing of regulatory T cells has emerged in directing effector T cell maturation. In the absence of functional Helios, effector T cells acquire more inflammatory phenotype and are prone to senescence. Loss of Helios expression disrupts the regulation of the germinal centre reaction, often resulting in either hypogammaglobulinemia or B cell autoimmunity. This review summarizes findings from studies in both mice and men offering a comprehensive understanding of the impact of the transcription factor Helios on the adaptive immune system.

Cabozantinib-encapsulated and maytansine-conjugated high-density lipoprotein for immunotherapy in colorectal cancer

Advanced colorectal cancer (CRC) responds poorly to current adjuvant therapies, partially due to its immunosuppressive intestinal microenvironment. We found that myeloid-derived suppressor cells (MDSCs) were enriched in orthotopic tumors due to treatment-induced succinate release, which activated tuft cells and upregulated interleukin 25 (IL-25) and interleukin 13 (IL-13). We engineered a cabozantinib (Cabo)-encapsulated and maytansine (DM1)-conjugated synthetic high-density lipoprotein (ECCD-sHDL) to modulate the tumor microenvironment. DM1 induced immunogenic cell death and promoted the maturation of dendritic cells. Meanwhile, Cabo alleviated DM1-induced succinate release, preventing tuft cell activation, downregulating IL-25 and IL-13 secretion, and reducing intratumoral MDSC infiltration. ECCD-sHDL increased the densities of active cytotoxic T lymphocytes (CTLs) and M1 macrophages in the tumors, effectively inhibiting tumor growth and metastasis, thereby prolonging survival in murine CRC models. Our study sheds light on the mechanism of treatment-induced immunosuppression in orthotopic CRC and demonstrates that this combinatorial therapy could be an effective treatment for CRC.

The Metformin Immunoregulatory Actions in Tumor Suppression and Normal Tissues Protection.

The immune system is the key player in a wide range of responses in normal tissues and tumors to anticancer therapy. Inflammatory and fibrotic responses in normal tissues are the main limitations of chemotherapy, radiotherapy, and also some newer anticancer drugs such as immune checkpoint inhibitors (ICIs). Immune system responses within solid tumors including anti-tumor and tumor-promoting responses can suppress or help tumor growth. Thus, modulation of immune cells and their secretions such as cytokines, growth factors and epigenetic modulators, pro-apoptosis molecules, and some other molecules can be suggested to alleviate side effects in normal tissues and drug-resistance mechanisms in the tumor. Metformin as an anti-diabetes drug has shown intriguing properties such as anti-inflammation, anti-fibrosis, and anticancer effects. Some investigations have uncovered that metformin can ameliorate radiation/chemotherapy toxicity in normal cells and tissues through the modulation of several targets in cells and tissues. These effects of metformin may ameliorate severe inflammatory responses and fibrosis after exposure to ionizing radiation or following treatment with highly toxic chemotherapy drugs. Metformin can suppress the activity of immunosuppressive cells in the tumor through the phosphorylation of AMP-activated protein kinase (AMPK). In addition, metformin may stimulate antigen presentation and maturation of anticancer immune cells, which lead to the induction of anticancer immunity in the tumor. This review aims to explain the detailed mechanisms of normal tissue sparing and tumor suppression during cancer therapy using adjuvant metformin with an emphasis on immune system responses.

A Multifunctional Biomimetic Nanoplatform for Dual Tumor Targeting-Assisted Multimodal Therapy of Colon Cancer.

The biomimetic nanoparticles (NPs) possessing abilities of tumor targeting and multimodal therapy show great potential for efficient combat of colon cancer. Herein, we developed a multifunctional biomimetic nanoplatform (Fe3O4@PDA@CaCO3-ICG@CM) based on CaCO3-modified magnetic polydopamine (PDA) loaded with indocyanine green (ICG), which was encapsulated by a mouse lymphoma cell (EL4) membrane (CM) expressing functional proteins (i.e., lymphocyte function-associated antigen 1, LFA-1; transforming growth factor-β receptor, TGF-βR; programmed cell death protein 1, PD-1; and factor related apoptosis ligand, FasL). Under magnetic attraction and LFA-1/PD-1-mediated endocytosis, Fe3O4@PDA@CaCO3-ICG@CM efficiently targeted CT26 colon tumor cells. The released calcium ion (Ca2+) from the NPs triggered by acidic tumor microenvironment, the enhanced photothermal effect contributed by the combination of PDA and ICG, and FasL's direct killing effect together induced tumor cells apoptosis. Moreover, the apoptosis of CT26 cells induced immunogenic cell death (ICD) to promote the maturation of dendritic cells (DCs) to activate CD4+/CD8+ T cells, thereby fighting against tumor cells, which could further be boosted by programmed death-ligand 1 (PD-L1) blockage and transforming growth factor-β (TGF-β) scavenging by Fe3O4@PDA@CaCO3-ICG@CM. As a result, in vivo satisfactory therapeutic effect was observed for CT26 tumor bearing-mice treated with Fe3O4@PDA@CaCO3-ICG@CM under laser irradiation and magnetic attraction, which could eradicate primary tumors and restrain distant tumors through dual tumor targeting-assisted multimodal therapy and eliciting adaptive antitumor immune response, generating the immune memory for inhibiting tumor metastasis and recurrence. Taken together, the multifunctional biomimetic nanoplatform exhibits superior antitumor effects, providing an insightful strategy for the field of nanomaterial-based treatment of cancer.

8037 Ciliopathy Genes are Expressed in the Developing Pituitary Gland and Mature Hormone-Producing Cells

8037 Ciliopathy Genes are Expressed in the Developing Pituitary Gland and Mature Hormone-Producing Cells

Metabolic modelling identifies mitochondrial Pi uptake and pyruvate efflux as key aspects of daytime metabolism and proton homeostasis in crassulacean acid metabolism leaves.

Crassulacean acid metabolism (CAM) leaves are characterized by nocturnal acidification and diurnal deacidification processes related with the timed actions of phosphoenolpyruvate carboxylase and Rubisco, respectively. How CAM leaves manage cytosolic proton homeostasis, particularly when facing massive diurnal proton effluxes from the vacuole, remains unclear. A 12-phase flux balance analysis (FBA) model was constructed for a mature malic enzyme-type CAM mesophyll cell in order to predict diel kinetics of intracellular proton fluxes. The charge- and proton-balanced FBA model identified the mitochondrial phosphate carrier (PiC, Pi/H+ symport), which provides Pi to the matrix to sustain ATP biosynthesis, as a major consumer of cytosolic protons during daytime (> 50%). The delivery of Pi to the mitochondrion, co-transported with protons, is required for oxidative phosphorylation and allows sufficient ATP to be synthesized to meet the high energy demand during CAM Phase III. Additionally, the model predicts that mitochondrial pyruvate originating from decarboxylation of malate is exclusively exported to the cytosol, probably via a pyruvate channel mechanism, to fuel gluconeogenesis. In this biochemical cycle, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) acts as another important cytosolic proton consumer. Overall, our findings emphasize the importance of mitochondria in CAM and uncover a hitherto unappreciated role in metabolic proton homeostasis.

Paclitaxel Prodrug Enables Glutathione Depletion to Boost Cancer Treatment.

Herein, we constructed a paclitaxel (PTX) prodrug (PA) by conjugating PTX with acrylic acid as a cysteine-depleting agent. The as-synthesized PA can assemble with diacylphosphatidylethanolamine-PEG2000 to form stable nanoparticles (PA NPs). After endocytosis into cells, PA NPs can specifically react with cysteine and trigger release of PTX for chemotherapy. On the other hand, the depletion of cysteine can greatly downregulate the intracellular content of glutathione and lead to oxidative stress outburst-provoking ferroptosis. The released PTX can elicit antitumor immune response by inducing immunogenic cell death, thus promoting dendritic cells maturation and cascaded cytotoxic T lymphocytes activation, which not only produces a robust immunotherapy effect but also synergizes the ferroptosis therapy by inhibiting cysteine transport via the release of interferon-γ in the activated immune system. As a result, PA NPs exhibit favorable in vitro and in vivo antitumor performance with reduced systemic toxicity. Our work highlights the potential of simple molecular design of prodrugs for enhancing the therapeutic efficacy toward malignant cancer.

Enhancing CAR-T Cell Therapy Against Solid Tumor by Drug-Free Triboelectric Immunotherapy

Chimeric antigen receptor (CAR) T cell therapy is a highly effective immunotherapy for hematological tumors, but its efficacy against most solid tumors remains challenging. Herein, a novel synergistic combination therapy of drug-free triboelectric immunotherapy and CAR-T cell therapy against solid tumor was proposed. A triboelectric nanogenerator (TENG) that can generate pulsed direct-current by coupling triboelectrification effect and electrostatic breakdown effect was fabricated. The TENG can generate up to 30 pulse direct-current peaks with peak current output ≈35μA in a single sliding to power the triboelectric immunotherapy. The pulsed direct-current stimulation induced immunogenic cell death of tumor cells (survival rate of 35.9%), which promoted dendritic cells maturation, accelerated the process of antigen presentation to CAR-T cells and enhanced the systemic adaptive immune response. Furthermore, triboelectric immunotherapy promoted M1-like macrophage polarization, reduced regulatory T cells differentiation and reprogrammed the tumor immunosuppressive microenvironment, which ultimately enhanced the efficacy of CAR-T cells to eradicate nearly 60% of NALM6 solid tumor mass. Notably, considering that triboelectric immunotherapy is a safe and effective drug-free antitumor strategy, the combined therapy did not increase the burden of double-medication on patients.

Unlocking the secrets of NPSLE: the role of dendritic cell-secreted CCL2 in blood-brain barrier disruption

BackgroundThis study employed RNA-seq technology and meta-analysis to unveil the molecular mechanisms of neuropsychiatric systemic lupus erythematosus (NPSLE) within the central nervous system.MethodsDownloaded transcriptomic data on systemic lupus erythematosus (SLE) from the Gene Expression Omnibus (GEO) and analyzed differential genes in peripheral blood samples of NPSLE patients and healthy individuals. Employed WGCNA to identify key genes related to cognitive impairment and validated findings via RNA-seq. Conducted GO, KEGG, and GSEA analyses, and integrated PPI networks to explore gene regulatory mechanisms. Assessed gene impacts on dendritic cells and blood-brain barrier using RT-qPCR, ELISA, and in vitro models.ResultsPublic databases and RNA-seq data have revealed a significant upregulation of CCL2 (C-C motif chemokine ligand 2) in the peripheral blood of both SLE and NPSLE patients, primarily secreted by mature dendritic cells. Furthermore, the secretion of CCL2 by mature dendritic cells may act through the RSAD2-ISG15 axis and is associated with the activation of the NLRs (Nod Like Receptor Signaling Pathway) signaling pathway in vascular endothelial cells. Subsequent in vitro cell experiments confirmed the high expression of CCL2 in peripheral blood dendritic cells of NPSLE patients, with its secretion being regulated by the RSAD2-ISG15 axis and inducing vascular endothelial cell pyroptosis through the activation of the NLRs signaling pathway. Clinical trial results ultimately confirmed that NPSLE patients exhibiting elevated CCL2 expression also experienced cognitive decline.ConclusionsThe secretion of CCL2 by dendritic cells induces pyroptosis in vascular endothelial cells, thereby promoting blood-brain barrier damage and triggering cognitive impairment in patients with systemic lupus erythematosus.

The Role of Gut Microbiota as a Trigger for Exacerbations in Pulmonary Obstruction Disorder in General

Pulmonary diseases can be associated with the gastrointestinal (GI) system, particularly if an infection causes them. This relationship between organs is known as the gut-lung axis (GLA). Skin and mucosal surfaces are associated with microbiota (bacteria, fungi, viruses, macrophages, archaea, protists, helminths), which can trigger an immune response in GLA and serve a role in respiratory diseases. For instance, asthma can be inhibited by a specific antigen that is triggered by probiotics, the microorganisms found in the GI tract. Asthma incidence can be reduced by consuming fiber due to its ability to protect airways from infection. Pattern recognition receptors (PRRs) are the first immune component to identify microbial compounds in GI and lung epithelial cells. The PRRs then induce regulatory T-cell (T-reg) and Th-17 differentiation. Diet, antibiotics, and stress can all influence the structure and function of bacteria. This is known as dysbiosis. Lung microbiota can influence immune cell maturation and homeostasis. If the diversity of lung microbiota decreases, it will affect intestinal microbiota and may result in chronic respiratory disorders such as chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis. This literature review explained how the interactions between the intestines and lungs can affect humans’ health and well-being.