Immunoregulatory Functions Research Articles

Evaluation of the effectiveness of cytotherapy in women with early pregnancy loss

Background: Cytotherapy, or alloimmunization, with partner lymphocytes is a method of active immunocorrection through artificial immunization with allogeneic paternal or donor leukocytes or their fragments before and in the early stages of pregnancy, as an effective method for correcting immunoregulation, which will increase the effectiveness of assisted reproductive technologies protocols and the number of successful pregnancies ending in live birth in couples with recurrent pregnancy loss. Aim: The aim of this study was to evaluate the clinical and laboratory effectiveness of cytotherapy in married couples with a history of reproductive disorders. Materials and methods: The study included 77 married couples with recurrent miscarriage, primary infertility, and repeated implantation failure during in vitro fertilization. Inclusion criteria were age 20–44 years, 2 implantation failures during in vitro fertilization and more and/or 2 spontaneous abortions before 20 weeks of gestation and more, normal karyotypes of the abortus and partners, HLA (human leukocyte antigen, major histocompatibility complex) class II gene typing at three loci (DQA1, DQB1, DRB1) in the married couple. All women received cytotherapy as monotherapy before a planned pregnancy. To study the immune status, the patients’ blood was examined and the natural killer (NK) cell (CD3−CD16+CD56+) and natural T-killer (NKT) cell (CD3+CD16+CD56+) counts, as well as NK cell activity, were determined by spontaneous or activated expression of CD107a. Results: Of the 77 women included in the study, 32 individuals did not have 12 months to register their pregnancy, therefore, of the remaining 48 married couples, 32 (66.7%) ones had pregnancy registered within 12 months after immunization. Among patients with recurrent miscarriage, pregnancy occurred in 87.0% of cases, in which in 45.2% of cases it ended in the birth of a healthy full-term newborn, and in 29% of cases, pregnancy is currently developing. Among patients with primary infertility and repeated implantation failure during in vitro fertilization, pregnancy occurred in 35.3% of cases. When comparing the functional activities of NK cells in peripheral blood before and two weeks after the second cytotherapy, we found a decrease in the total NK cell count by 5.1% (p = 0.015). Conclusions: Cytotherapy is an effective therapy in patients with recurrent early miscarriage and leads to pregnancy in 87% of cases and its prolongation after 13 weeks in 74% of cases. The effect of the procedure is justified by its immunoregulatory functions, which is manifested by a decrease in the total NK cell count.

Insight into the anti-allergic impacts of fucoidan from Gracilaria lemaneiformis in mitigating allergic reactions induced by shrimp tropomyosin via regulating Th1/Th2 cytokines and T cell subsets.

Fucoidan is a natural sulfated polysaccharide with immunoregulatory function. In this work, the anti-allergic impacts of Gracilaria lemaneiformis fucoidan (GLF) in mitigating allergic reactions induced by shrimp tropomyosin were investigated. As the results, GLF performed significant hyaluronidase inhibition ability (IC50 = 0.272 mg/mL), alleviated the allergic reactions of RAW 264.7 macrophage cells via decreasing the secretion of TNF-α and NO by 58.75 % and 46.17 %, respectively, and mitigated the degranulation degree and secretion of IL-4, TNF-α and histamine as well as promoted IL-10 secretion in RBL-2H3 mast cells. In BALB/c mouse, after gavage of GLF, the mouse allergic symptoms got significantly alleviated, the secretion of IgE and IgG1 got reduced, IgG2a got promoted, the IL-4 secretion from mouse spleen lymphocytes (SLP) significantly declined, and IL-10 and IFN-γ secretion in SLP got improved, which indicated GLF performed significantly anti-allergic functions via transforming Th2 response into Th1 and Treg response. Moreover, the SLP cells treated by GLF had lower expression of GATA-3, higher T-bet and Foxp3 expression, which indicated GLF could mitigate allergic reactions via regulating T-bet, GATA3 and Foxp3 transcription factor expression of T cell subsets. Therefore, GLF could serve as anti-allergic substances for shrimp-induced allergy via regulating Th1/Th2 cytokines and T cell subsets.

Circadian Rhythm Disruption Exacerbates Autoimmune Uveitis: The Essential Role of PER1 in Treg Cell Metabolic Support for Stability and Function.

Circadian rhythm plays a critical role in the progression of autoimmune diseases. While our previous study demonstrated the therapeutic effects of melatonin in experimental autoimmune uveitis, the involvement of circadian rhythm remained unclear. Using a light-induced circadian rhythm disruption model, we showed that disrupted circadian rhythms exacerbate autoimmune uveitis by impairing the stability and function of Treg cells. Mechanistically, we identified the core clock gene Per1, which is significantly reduced under circadian disruption, is essential for Treg cell metabolism and immunoregulatory function. This study underscores the pivotal role of circadian rhythm-related Treg cells in autoimmune disease progression.

Combination of rapamycin and adipose-derived mesenchymal stromal cells enhances therapeutic potential for osteoarthritis

BackgroundThe regenerative potential of mesenchymal stromal/stem cells (MSCs) has been extensively studied in clinical trials in the past decade. However, despite the promising regenerative properties documented in preclinical studies, for instance in osteoarthritis (OA), the therapeutic translation of these results in patients has not been fully conclusive. One factor contributing to this therapeutic barrier could be the presence of senescent cells in OA joints.MethodsThis study evaluated a novel approach to OA treatment by combining adipose tissue-derived MSCs (AD-MSCs) with rapamycin, a clinically approved immunosuppressive drug with anti-senescence properties. First, rapamycin effects on senescence and fibrosis markers were investigated in freshly isolated OA chondrocytes by immunostaining. Next, the in vitro differentiation capacities of AD-MSCs, their regulatory immune functions on activated immune cells and their regenerative effects on OA chondrocyte signature were assessed in the presence of rapamycin.ResultsIn OA chondrocytes, rapamycin reduced the senescence marker p15INK4B and the fibrosis marker COL1A1 without affecting the expression of the master chondrogenic markers SOX9 and COL2. Rapamycin also enhanced AD-MSC differentiation into chondrocytes and reduced their differentiation into adipocytes. In addition, rapamycin improved AD-MSC immunoregulatory functions by promoting the expression of immunosuppressive factors, such as IDO1, PTGS2 and also CD274 (encoding PD-L1). Finally, RNA sequencing analysis showed that in the presence of rapamycin, AD-MSCs displayed improved chondroprotective regenerative effects on co-cultured OA chondrocytes.ConclusionsOur findings suggest that the rapamycin and AD-MSC combination enhances the therapeutic efficacy of these cells in senescence-driven degenerative diseases such as OA, notably by improving their anti-fibrotic and anti-inflammatory properties.Graphical abstract

Host-virus interactions during infection with a wild-type ILTV strain or a glycoprotein G deletion mutant ILTV vaccine strain in an ex vivo system.

Previous studies have demonstrated the safety and efficacy of a live-attenuated glycoprotein G (gG) deletion mutant vaccine strain of ILTV (∆gG-ILTV). In the current study, transcriptional profiles of chicken tracheal organ cultures (TOCs), 24 h post inoculation with ∆gG-ILTV or the gG-expressing parent wild-type strain, CSW-1 ILTV were explored and compared with the mock-infected TOCs using RNA-seq analysis. Transcriptomes of the vaccine and wild-type ILTV were also compared with each other. Although no viral genes (except for gG) were differentially regulated between the two ILTV-infected TOCs, pair-wise comparison of the transcriptomes of the ∆gG-ILTV or the CSW-1 ILTV-infected TOCs (each compared with mock-infected TOCs) identified the similarities and differences in host gene transcription between them. Several immune checkpoint inhibitors with likely roles in ILTV-mediated immune augmentation, and gene ontologies indicating cytokine response, and cytokine signaling were upregulated in both TOCs. Additionally, several other biological processes, molecular functions, and cellular components were enriched uniquely in the ∆gG-ILTV-infected TOCs, including those that indicated modifications to tracheal extracellular matrix (ECM) structural components, which may have a role in immune modulation in vivo. This study has revealed that the modifications of transcription of host genes during the early stages of ILTV infection are not limited to changes in cytokine or chemokine gene transcription, but several other immune-related genes and ECM components. Moreover, their differential regulation in the ex vivo system appears to be influenced by gG expression, potentially affecting the outcome of ILTV infection in vivo.IMPORTANCEInfectious laryngotracheitis virus (ILTV) remains a serious threat to poultry industries worldwide, causing significant economic losses. The glycoprotein G (gG) of ILTV is a virulence factor and a chemokine-binding protein with immunoregulatory functions. The influence of gG on the transcription of select host chemokine and cytokine genes has been demonstrated previously. This study extends our understanding of the early and localized host-ILTV interactions using genome-wide transcriptome analysis of ILTV-infected chicken tracheal organ cultures, and the role of gG during the process. Differential regulation of genes encoding immune checkpoint inhibitors observed in this study may have a role in ILTV-induced inhibition of type I interferon response, or negative regulation of T cell responses, bringing clarity to these ILTV immune-evasion mechanisms. Furthermore, differential regulation of genes encoding certain structural components and receptors with roles in cell migration, in the absence of gG, is consistent with the immunomodulatory role of ILTV gG.

Fasciola gigantica Recombinant Abelson Tyrosine Protein Kinase (rFgAbl) Regulates Various Functions of Buffalo Peripheral Blood Mononuclear Cells.

Fasciola gigantica can modulate host immune mechanisms through excretory-secretory products (ESP). As one of the components of ESP, it is unknown whether Abelson tyrosine protein kinase (Abl) is involved in parasite-host immune interaction. To investigate the immunoregulatory function of Abl in Fasciola gigantica, we cloned and expressed the Fasciola gigantica Abl protein and assessed its effect on specific immune functions of buffalo peripheral blood mononuclear cells (PBMCs). Recombinant F. gigantica Abelson tyrosine protein kinase (rFgAbl) was expressed in Escherichia coli. Western blot analysis was performed to assess the reactivity of anti-rFgAbl antibodies with rFgAbl, serum from F. gigantica-infected buffalo, and excretion and secretion products of F. gigantica. Immunohistochemical analysis was conducted to determine the localization of FgAbl in tissues from larval stages and adult worms of F. gigantica. Furthermore, immunofluorescence analysis was utilized to evaluate the binding ability of the rFgAbl protein to buffalo peripheral blood mononuclear cells (PBMCs), as well as to investigate the effects of varying concentrations of rFgAbl protein (5, 10, 20, 40, and 80 μg/mL) on the functional responses of PBMCs. Anti-rFgAbl antibodies specifically recognize rFgAbl, serum from buffalo infected with F. gigantica, and FgESP. rFgAbl is localized in the cecum and capsule of juvenile worms, as well as in the testis and viellaria of adult worms. Additionally, rFgAbl enhances cell proliferation, migration, nitric oxide (NO) production, and phagocytosis, while also increasing the transcription levels of cytokines (IFN-γ, IL-12, TNF-α, IL-4, IL-10, and TGF-β). The results indicate that rFgAbl can influence the immune function of PBMCs. Further investigation into the immunomodulatory properties of the rFgAbl protein will enhance our understanding of the immune interaction mechanisms between trematodes and their hosts.

Roles for Exosomes in the Pathogenesis, Drug Delivery and Therapy of Psoriasis.

Psoriasis is a chronic, recurrent and inflammatory skin disease. Although conventional immunosuppressants can ameliorate psoriatic symptoms, it tends to relapse over time. Previous studies have shown that exosomes from both immune and non-immune cells participate in psoriatic immunopathology. The biologically active cargoes in exosomes accelerate psoriasis progression by altering gene profiles and signaling pathways of neighboring cells. On the other hand, exosomes can be utilized as drug delivery platforms for psoriasis treatment. Especially, engineered exosomes may serve as drug delivery systems for effective delivery of proteins, nucleic acids or other drugs due to their low immunogenicity, good stability and ability to fuse with target cells. Therefore, investigation into the mechanisms underlying intercellular communications mediated by exosomes in skin lesions likely helps design drugs for therapy of psoriasis. In this review, we have summarized recent advances in the biogenesis of exosomes and their potential roles in the pathogenesis and treatment of psoriasis and further discussed their challenges and future directions in psoriasis treatment. In particular, this review highlights the immunoregulatory function of exosomes derived from immune or non-immune cells and exosome-based therapeutic applications in psoriasis, including their drug delivery systems. Thus, this review may help accelerate applications of exosomes for drug delivery and treatment of psoriasis.

Safety, Tolerability, and Pharmacokinetics of NIM-1324 an Oral LANCL2 Agonist in a Randomized, Double-Blind, Placebo-Controlled Phase I Clinical Trial.

NIM-1324 is an oral investigational new drug for autoimmune disease that targets the Lanthionine Synthetase C-like 2 (LANCL2) pathway. Through activation of LANCL2, NIM-1324 modulates CD4+ T cells to bias signaling and cellular metabolism toward increased immunoregulatory function while providing similar support to phagocytes. In primary human immune cells, NIM-1324 reduces type I interferon and inflammatory cytokine (IL-6, IL-8) production. Oral NIM-1324 was assessed for safety, tolerability and PK in normal healthy volunteers in a randomized, double-blind, placebo-controlled trial. Subjects (n = 57) were randomized into five single ascending dose (SAD) cohorts (250, 500, 750, 1000, 1500 mg, p.o.) and three multiple ascending dose (MAD) cohorts (250, 750, 1500 mg QD for 7 days, p.o.). NIM-1324 did not increase total AE rates in individual cohorts or pooled active groups in SAD or MAD with no SAEs in the study. Oral NIM-1324 dosing does not result in any clinically significant findings by biochemistry, coagulation, ECG, hematology, or urinalysis when compared to placebo. Plasma exposure, as measured by area under the curve from 0 to 24 h (AUC0-24), scaled dose proportionally over 250-1000 mg. At 250 mg, NIM-1324 successfully engaged the target with an upregulation of Lancl2 and key transcriptional biomarkers in whole blood. In conclusion, NIM-1324 treatment is well-tolerated up to daily oral doses of at least 1500 mg (nominal), a ≥ six-fold margin over the anticipated therapeutic dose, and 1000 mg (maximum observed exposure), at least a four-fold margin over the anticipated therapeutic dose with no dose limiting toxicities.

Progesterone regulates gut microbiota mediating bone marrow mesenchymal stem cell injury in immune thrombocytopenia patients during pregnancy.

Immune thrombocytopenia during pregnancy (PITP) is the most common cause of platelet reduction in early and mid-pregnancy. However, the pathogenesis of PITP is still unclear. To determine the characteristics of bone marrow mesenchymal stem cells (BM-MSCs) in PITP patients and to explore the associations between metabolites, the gut microbiota, and BM-MSCs in PITP. The characteristics of BM-MSCs were detected through invitro and invivo experiments. Nontargeted metabolomics was used to screen metabolites. The features of the gut microbiota were analyzed by 16S rDNA sequencing. PITP and fecal microbiota transplantation (FMT) mouse model were established to explore the associations between metabolites, gut microbiota, and BM-MSCs. BM-MSCs from PITP patients had significant senescence and apoptosis, as well as impaired immunoregulatory function. Metabolomic analysis indicated that progesterone was the most significant specific metabolite in PITP patients. Invivo studies showed that progesterone mediated MSC injury. Further analysis of the gut microbiota and FMT experiments revealed that progesterone mediated BM-MSCs injury by regulating the composition of the gut microbiota in PITP. RNA sequencing analysis of BM-MSCs from FMT mice revealed abnormal expression of genes related to cell aging and the NOD-like receptor signaling pathway. In conclusion, BM-MSCs in the PITP were significantly impaired, which was associated with increased progesterone and changes in the gut microbiota regulated by progesterone. Intervening with the gut microbiota may become a new treatment for PITP.

Skin collagen peptides of Chinese giant salamander (Andrias davidianus) exert anti-inflammatory effects in LPS-induced RAW264.7 cells via the lincRNA-EPS/NF-κB pathway

ABSTRACT Food-derived collagen peptides have recently been reported to have immunomodulatory functions. The Chinese giant salamander (CGS) has both edible and medicinal values. In this study, we tried to verify the immunoregulatory function of CGS skin collagen peptides (CGSSCPs) on macrophages and elucidate its mechanism. CGSSCPs decreased the secretion of nitric oxide (NO) and downregulated the expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α), chemokine (C–C motif) ligand 5 (CCL5) and (C-X-C motif) ligand 10 (CXCL10) in Lipopolysaccharide (LPS)-induced RAW264.7 cells. Moreover, CGSSCPs promoted the expression of lincRNA-EPS, and inhibited the phosphorylation of nuclear factor kappa-B (NF-κB) in LPS-induced RAW264.7 cells. Silencing lincRNA-EPS up-regulated the phosphorylation level of NF-κB and the expression of inflammatory cytokines (IL-6, IL-1β, and TNF-α) and chemokines (CCL5 and CXCL10). These suggest that CGSSCPs may regulate RAW264.7 cells by the lincRNA-EPS/NF-κB pathway, which provides a theoretical basis for the development of new anti-inflammatory drugs.

Long-term hypoxic atmosphere enhances the stemness, immunoregulatory functions, and therapeutic application of human umbilical cord mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are usually cultured in a normoxic atmosphere (21%) in vitro, while the oxygen concentrations in human tissues and organs are 1% to 10% when the cells are transplanted in vivo. However, the impact of hypoxia on MSCs has not been deeply studied, especially its translational application. In the present study, we investigated the characterizations of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in hypoxic (1%) and normoxic (21%) atmospheres with a long-term culture from primary to 30 generations, respectively. The comparison between both atmospheres systematically analyzed the biological functions of MSCs, mainly including stemness maintenance, immune regulation, and resistance to chondrocyte apoptosis, and studied their joint function and anti-inflammatory effects in osteoarthritis (OA) rats constructed by collagenase II. We observed that long-term hypoxic culture surpassed normoxic atmosphere during hUC-MSCs culture in respect of promoting proliferation, anti-tumorigenicity, maintaining normal karyotype and stemness, inhibiting senescence, and improving immunoregulatory function and the role of anti-apoptosis in chondrocytes. Furthermore, we demonstrated that the transplantation of long-term hypoxic hUC-MSCs (Hy-MSCs) had a better therapeutic effect on OA rats compared with the hUC-MSCs cultured in the normoxic atmosphere (No-MSCs) in terms of the improved function and swelling recovery in the joints, and substantially inhibited the secretion of pro-inflammatory factors, which effectively alleviated cartilage damage by reducing the expression of matrix metallopeptidase 13 (MMP-13). Our results demonstrate that Hy-MSCs possess immense potential for clinical applications via promoting stemness maintenance and enhancing immunoregulatory function.

In situ licensing of mesenchymal stem cell immunomodulatory function via BMP-2 induced developmental process

The immunomodulatory function of mesenchymal stem cells (MSCs) is plastic and susceptible to resident microenvironment in vivo or inflammatory factors in vitro. We propose a unique method to enhance the immunoregulatory functions of mesenchymal stem cells (MSCs) through an artificially controllable in vivo inflammatory microenvironment generated by biomaterials loaded with BMP-2 that induce bone development. MSCs activated through this method effectively induce M1 macrophage polarization toward the M2 phenotype, promote differentiation of naïve T cells into regulatory T cells, and inhibit the proliferation of activated T cells via prostaglandin E2 (PGE2) secretion. This in vivo licensing not only preserves the immunogenicity of MSCs but also alters DNA methylation patterns, enabling MSCs to exhibit immunoregulatory effects with epigenetic memory. Validation in a mouse colitis model demonstrated their therapeutic efficacy and long-term viability. Furthermore, we found that the material composition influences the inflammatory response during development, with polysaccharide-based biomaterials proving advantageous over protein-based materials in establishing an inflammatory niche conducive to MSC activity. These findings underscore the potential of tissue engineering to create in vivo environments that license MSCs, offering a strategic avenue to enhance MSC-based therapies for addressing significant immune disorders.

Participation of Semaphorin Family and Plexins in the Clinical Course of Patients with Inflammatory Bowel Disease.

Characterize the semaphorins and plexins gene and protein expression in intestinal tissue from IBD patients and correlate them with the clinical phenotype. This comparative and cross-sectional study enrolled 54 diagnosed IBD patients and 20 controls. Gene and protein expression of semaphorins and plexins were determined by RT-PCR and IHQ for the co-localization with neutrophils (myeloperoxidase, MPO) or CD123 plasmacytoid dendritic cells in intestinal tissue from IBD patients. Colonic mucosa from active and remission ulcerative colitis (UC) had a significantly lower SEMA4D and PLXNA1, but higher PLXNB1 gene expression than the control group. The only significant difference between active UC and remission was observed in the higher gene expression of SEMA6D in remission. It was associated with histological remission (p = 0.01, OR = 15, 95% CI: 1.39-16.1). The low expression of PLXNA1 was associated with mild intermittent activity with two relapses per year (p = 0.003, OR = 0.05, CI = 0.006-0.51). Higher SEMA4D+ positive cells were detected in the submucosa, while PLXNC1+/MPO+ in the mucosal and submucosa of active UC patients compared with controls. The increased expression of the semaphorin and plexin family in IBD patients suggests their immunoregulatory function and is associated with remission and clinical phenotype in patients with UC.

Single cell profiling of hematopoietic stem cell transplant recipients reveals TGF-β1 and IL-2 confer immunoregulatory functions to NK cells

Single cell profiling of hematopoietic stem cell transplant recipients reveals TGF-β1 and IL-2 confer immunoregulatory functions to NK cells

Immunological face of megakaryocytes.

Megakaryocytes (MKs), which are traditionally known for their role in platelet production, are now emerging as unique immune cells with diverse capabilities. They express immune receptors, participate in pathogen recognition and response, phagocytose pathogens, contribute to antigen presentation, and interact with various immune cell types. When encountering inflammatory challenges, MKs exhibit intricate immune functions that can either promote or inhibit inflammation. These responses are mediated through mechanisms, such as the secretion of either anti-inflammatory or pro-inflammatory cytokines and release of immunomodulatory platelets according to specific conditions. This intricate array of responses necessitates a detailed exploration to determine whether the immune functions of MKs are carried out by the entire MK population or by a specific subpopulation. Breakthroughs in single-cell RNA sequencing have uncovered a unique "immune MK" subpopulation, revealing its distinct characteristics and immunoregulatory functions. This review provides latest insights into MKs' immune attributes and their roles in physiological and pathological contexts and emphasizes the discovery and functions of "immune MKs".

Erythrocyte Selenium as a Potential Key Indicator for Selenium Supplementation in Low-Selenium Populations: A Selenium Supplementation Study Based on Wistar Rats.

Selenium (Se) is an essential trace element for maintaining human health, with significant antioxidant and immunoregulatory functions. Inadequate Se intake may be associated with Keshan disease, Kashin-Beck disease, and hypothyroidism. However, effective indicators for scientifically guiding Se supplementation in Se-deficient populations are still lacking. This study aims to explore the dynamic distribution of Se across various nutritional biomarkers and major organs in rats through a Se supplementation experiment, as well as the pairwise correlations between them, in order to identify reliable nutritional indicators for evaluating Se levels in the body. Se levels in hair, blood, and major tissues and organs were determined by atomic fluorescence spectrometry, and glutathione peroxidase (GSH-Px) levels were measured using an ELISA. Se supplementation significantly increased Se levels in rat blood, hair, and major organs, as well as GSH-Px levels in blood. Se primarily accumulated in the liver and kidneys, followed by myocardium, spleen, and muscles. Serum and plasma Se were found to be the best indicators of short-term Se intake, while erythrocyte Se levels showed a stronger correlation with Se levels in tissues and organs, making it a better marker for assessing long-term Se nutritional status compared to hair Se. This study demonstrates the potential of erythrocyte Se levels as an indicator for evaluating long-term Se nutritional status, providing scientific evidence for Se nutritional assessments.

Activation of α2B/2C adrenergic receptor ameliorates ocular surface inflammation through enhancing regulatory T cell function

There is an unmet need for effectively treating dry eye disease (DED), a T cell-mediated chronic, inflammatory ocular surface disorder. Given the potential of nonneuronal adrenergic system in modulating T cell response, we herein investigated the therapeutic efficacy and the underlying mechanisms of a specific alpha 2 adrenergic receptor agonist (AGN-762, selective for α2B/2C receptor subtypes) in a mouse model of DED. Experimental DED was treated with the AGN-762 by oral gavage, either at disease induction or after disease establishment, and showed sustained amelioration, along with reduced expression of DED-pathogenic cytokines in ocular surface tissues, decreased corneal MHC-II+CD11b+ cells and lymphoid Th17 cells, and higher function of regulatory T cells (Treg). In vitro culture of DED-derived effector T helper cells (Teff) with AGN-762 failed to suppress Th17 response, while culture of DED-Treg with AGN-762 led to enhanced suppressive function of Treg and their IL-10 production. Adoptive transfer of AGN-762-pretreated DED-Treg in syngeneic B6.Rag1-/- mice effectively suppressed DED Teff-mediated disease and Th17 response, and the effect was abolished by the neutralization of IL-10. In conclusion, our findings demonstrate that α2B/2C adrenergic receptor agonism effectively ameliorates persistent corneal epitheliopathy in DED by enhancing IL-10 production from Treg and thus restoring their immunoregulatory function.

Itaconate uptake via SLC13A3 improves hepatic antibacterial innate immunity.

Itaconate is an immunoregulatory metabolite produced by the mitochondrial enzyme immune-responsive gene 1 (IRG1) in inflammatory macrophages. We recently identified an important mechanism by which itaconate is released from inflammatory macrophages. However, it remains unknown whether extracellular itaconate is taken up by non-myeloid cells to exert immunoregulatory functions. Here, we used a custom-designed CRISPR screen to identify the dicarboxylate transporter solute carrier family 13 member 3 (SLC13A3) as an itaconate importer and to characterize the role of SLC13A3 in itaconate-improved hepatic antibacterial innate immunity. Functionally, liver-specific deletion of Slc13a3 impairs hepatic antibacterial innate immunity invivo and invitro. Mechanistically, itaconate uptake via SLC13A3 induces transcription factor EB (TFEB)-dependent lysosomal biogenesis and subsequently improves antibacterial innate immunity in mouse hepatocytes. These findings identify SLC13A3 as a key itaconate importer in mouse hepatocytes and will aid in the development of potent itaconate-based antibacterial therapeutics.

Enhancing Bone-Titanium integration through hydrogel coating mediated sequential M1/M2 polarization of interfacial macrophages

Regulating phenotypes of in situ macrophages (Mφ) is a cutting-edge strategy for promoting bone-Titanium (Ti) integration, but what is the most rational modulation manner has long been controversial. Short-term inducing in situ M1 Mφ polarization or inducing in situ M2 Mφ polarization have proven to be capable of promoting osseointegration. However, an increasing number of researches have claimed that sequentially inducing in situ M1/M2 Mφ polarization, compared to the above-mentioned two strategies, could further enhance osseointegration. In this work, we compared the capability of the three different modulation manners to promote osseointegration. Briefly, we anchored a homogeneous Poly(HEMA-co-3APBA)/LUT/SOP hydrogel coating, which could sequentially release pro-inflammatory sophoridine (SOP) molecules and anti-inflammatory luteolin (LUT) molecules through pH mediated conformational transition of phenylboronic acid ester bonds, on the surface of Ti implants. Ti implants coated with the Poly(HEMA-co-3APBA)/SOP hydrogel or the Poly(HEMA-co-3APBA)/LUT hydrogel, which merely released SOP molecules and LUT molecules respectively, were utilized as controls. In vitro Mφ co-culture assays proved the immunoregulation functions of different hydrogel coatings in inducing Mφ polarization, and the rationale behind which was identified to be related to the PI3K-AKT signaling pathways. In addition, the immunoregulation mediated osteogenic differentiation behaviors of bone marrow mesenchymal stem cells (BMSCs) were also investigated. Implantation of as-prepared Ti nails to a rat femur defect model followed by evaluations of H&E staining, Masson staining, immunohistochemical staining, etc. proved the stronger capability to enhance osseointegration of inducing sequential M1/M2 Mφ polarization than short-term inducing in situ M1 Mφ polarization or inducing in situ M2 Mφ polarization. This work not only reported a novel Ti implant with superior osseointegration capability but also will inspire corresponding researches in the future.

Immunoregulation and male reproductive function: Impacts and mechanistic insights into inflammation.

This paper investigates the complex relationship between the immune system and male reproductive processes, emphasizing how chronic inflammation can adversely affect male reproductive health. The immune system plays a dual role; it protects and regulates reproductive organs and spermatogenesis while maintaining reproductive health through immune privilege in the testes and the activities of various immune cells and cytokines. However, when chronic inflammation persists or intensifies, it can disrupt this balance, leading to immune attacks on reproductive tissues and resulting in infertility.This study provides a detailed analysis of how chronic inflammation can impair sperm production, sperm quality, and the secretion of gonadal hormones both directly and indirectly. It also delves into the critical roles of testicular immune privilege, various immune cells, and cytokines in sustaining reproductive health and examines the impacts of infections, autoimmune diseases, and environmental factors on male fertility.