Immune Regulation Research Articles

Advanced nanomedicines and immunotherapeutics to treat respiratory diseases especially COVID-19 induced thrombosis

Immunotherapy and associated immune regulation strategies gained huge attraction in order to be utilized for treatment and prevention of respiratory diseases. Engineering specifically nanomedicines can be used to regulate host immunity in lungs in the case of respiratory diseases including coronavirus disease 2019 (COVID-19) infection. COVID-19 causes pulmonary embolisms, thus new therapeutic options are required to target thrombosis, as conventional treatment options are either not effective due to the complexity of the immune-thrombosis pathophysiology. In this review, we discuss regulation of immune response in respiratory diseases especially COVID-19. We further discuss thrombosis and provide an overview of some antithrombotic nanoparticles, which can be used to develop nanomedicine against thrombo-inflammation induced by COVID-19 and other respiratory infectious diseases. We also elaborate the importance of immunomodulatory nanomedicines that can block pro-inflammatory signalling pathways, and thus can be recommended to treat respiratory infectious diseases.

Investigating the Influence of Gut Microbiota-related Metabolites in Gastrointestinal Cancer.

Gastrointestinal (GI) cancer is a major health concern due to its prevalence, impact on well-being, high mortality rate, economic burden, and potential for prevention and early detection. GI cancer research has made remarkable strides in understanding biology, risk factors, and treatment options. An emerging area of research is the gut microbiome's role in GI cancer development and treatment response. The gut microbiome, vital for digestion, metabolism, and immune function, is increasingly linked to GI cancers. Dysbiosis and alterations in gut microbe composition may contribute to cancer development. Scientists study how specific bacteria or microbial metabolites influence cancer progression and treatment response. Modulating the gut microbiota shows promise in enhancing treatment efficacy and preventing GI cancers. Gut microbiota dysbiosis can impact GI cancer through inflammation, metabolite production, genotoxicity, and immune modulation. Microbes produce metabolites like short-chain fatty acids, bile acids, and secondary metabolites. These affect host cells, influencing processes like cell proliferation, apoptosis, DNA damage, and immune regulation, all implicated in cancer development. This review explores the latest research on gut microbiota metabolites and their molecular mechanisms in GI cancers. The hope is that this attempt will help in conducting other relevant research to unravel the precise mechanism involved, identify microbial signatures associated with GI cancer, and develop targets.

Targeting BTLA with the peptide inhibitor HVEM(14-39) – A new way to restore the activity of T cells in melanoma

The complex of B- and T-lymphocyte attenuator (BTLA) and herpes virus entry mediator (HVEM) plays a critical role in immune regulation and has emerged as a promising therapeutic target for cancer treatment. In this study, we investigated the potential of the peptide inhibitor HVEM(14-39) to restore peripheral T cell activity in patients with advanced melanoma. In these patients, CD8+ T cells downregulated BTLA expression and increased HVEM expression upon activation. The addition of HVEM(14-39) reduced the percentage of BTLA+ CD8+ T cells and increased the subpopulation of HVEM+ CD8+ T cells. Additionally, HVEM(14-39) enhanced T cell activation, proliferation, and the shift toward effector memory T cell subpopulations. Finally, this peptide affected the proliferation rate and late apoptosis of melanoma cell line in co-culture with T cells. These findings suggest that HVEM(14-39) can overcome T cell exhaustion and improve antitumor responses. Peptide-based immunotherapy targeting the BTLA-HVEM complex offers a promising alternative to monoclonal antibody-based therapies, with the potential for fewer side effects and higher treatment efficacy.

Maternal age is related to offspring DNA methylation: A meta-analysis of results from the PACE consortium.

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5-10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR < 0.05). Eight of these CpGs were located near/in the MTNR1B gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near MTNR1B, at which higher DNAm was associated with greater maternal age (PFDR = 6.92 × 10-8) in newborns. In childhood blood samples, these differences in blood DNAm of MTNR1B CpGs were nominally significant (p < 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in RTEL1-TNFRSF6B at birth (PFDR < 0.05) and nominally in childhood (p < 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in YPEL3/BOLA2B in external data was associated with expression of ITGAL, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health.

Aquaporins in colorectal cancer: exploring their role in tumorigenesis, metastasis, and drug response.

Aquaporins (AQPs) are small, integral proteins facilitating water transport across plasma cell membranes in response to osmotic gradients. This family has 13 unique members (AQP0-12), which can also transport glycerol, urea, gases, and other salute small molecules. AQPs play a crucial role in the regulation of different cellular processes, including metabolism, migration, immunity, barrier function, and angiogenesis. These proteins are found to aberrantly overexpress in various cancers, including colorectal cancer (CRC). Growing evidence has explored AQPs as a potential diagnostic biomarker and therapeutic target in different cancers. However, there is no comprehensive review compiling the available information on the crucial role of AQPs in the context of colorectal cancer. This review highlights the significance of AQPs as the biomarker and regulator of tumor cells metabolism. In addition, the proliferation, angiogenesis, and metastasis of tumor cells related to AQPs expression as well as function are discussed. Understanding the AQPs prominent role in chemotherapy resistance is of great importance clinically.

The protein phosphatase PP6 promotes RIPK1-dependent PANoptosis

BackgroundThe innate immune system serves as the first line of host defense. Transforming growth factor-β–activated kinase 1 (TAK1) is a key regulator of innate immunity, cell survival, and cellular homeostasis. Because of its importance in immunity, several pathogens have evolved to carry TAK1 inhibitors. In response, hosts have evolved to sense TAK1 inhibition and induce robust lytic cell death, PANoptosis, mediated by the RIPK1-PANoptosome. PANoptosis is a unique innate immune inflammatory lytic cell death pathway initiated by an innate immune sensor and driven by caspases and RIPKs. While PANoptosis can be beneficial to clear pathogens, excess activation is linked to pathology. Therefore, understanding the molecular mechanisms regulating TAK1 inhibitor (TAK1i)-induced PANoptosis is central to our understanding of RIPK1 in health and disease.ResultsIn this study, by analyzing results from a cell death-based CRISPR screen, we identified protein phosphatase 6 (PP6) holoenzyme components as regulators of TAK1i-induced PANoptosis. Loss of the PP6 enzymatic component, PPP6C, significantly reduced TAK1i-induced PANoptosis. Additionally, the PP6 regulatory subunits PPP6R1, PPP6R2, and PPP6R3 had redundant roles in regulating TAK1i-induced PANoptosis, and their combined depletion was required to block TAK1i-induced cell death. Mechanistically, PPP6C and its regulatory subunits promoted the pro-death S166 auto-phosphorylation of RIPK1 and led to a reduction in the pro-survival S321 phosphorylation.ConclusionsOverall, our findings demonstrate a key requirement for the phosphatase PP6 complex in the activation of TAK1i-induced, RIPK1-dependent PANoptosis, suggesting this complex could be therapeutically targeted in inflammatory conditions.

Mechanisms of Male Reproductive Sterility Triggered by Dysbiosis of Intestinal Microorganisms

Abstract: The intestinal microbiota, comprised of bacteria, archaea, and phages, inhabits the gastrointestinal tract of the organism. Male reproductive sterility is currently a prominent topic in medical research. Increasing research suggests that gut microbiota dysbiosis can result in various reproductive health problems. This article specifically investigates the impact of gut microbiota dysbiosis on male reproductive infertility development. Gut microbiota imbalances can disrupt the immune system and immune cell metabolism, affecting testicular growth and sperm production. This dysfunction can compromise the levels of hormones produced and secreted by the endocrine glands, affecting male reproductive health. Furthermore, imbalance of the gut microbiota can disrupt the gut–brain–reproductive axis, resulting in male reproductive infertility. This article explores how the imbalance of the gut microbiota impacts male reproductive infertility through immune regulation, endocrine regulation, and interactions of the gut–brain–reproductive axis, concluding with recommendations for prevention and treatment.

Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade.

The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance. Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8+ T cells. Of these immunosuppressive cell types, PD-L1-expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Disruption of the epithelial cell clock regulates the secretion of cytokines that promote heightened inflammation, recruitment of neutrophils and the subsequent development of MDSCs. We also show that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, these data indicate that circadian gating of tumor immunosuppression informs the timing and efficacy of immune checkpoint inhibitors.

The mechanisms of white matter injury and immune system crosstalk in promoting the progression of Parkinson’s disease: a narrative review

Parkinson’s disease (PD) is neurodegenerative disease in middle-aged and elderly people with some pathological mechanisms including immune disorder, neuroinflammation, white matter injury and abnormal aggregation of alpha-synuclein, etc. New research suggests that white matter injury may be important in the development of PD, but how inflammation, the immune system, and white matter damage interact to harm dopamine neurons is not yet understood. Therefore, it is particularly important to delve into the crosstalk between immune cells in the central and peripheral nervous system based on the study of white matter damage in PD. This crosstalk could not only exacerbate the pathological process of PD but may also reveal new therapeutic targets. By understanding how immune cells penetrate through the blood–brain barrier and activate inflammatory responses within the central nervous system, we can better grasp the impact of structural destruction of white matter in PD and explore how this process can be modulated to mitigate or combat disease progression. Microglia, astrocytes, oligodendrocytes and peripheral immune cells (especially T cells) play a central role in its pathological process where these immune cells produce and respond to pro-inflammatory cytokines such as tumor necrosis factor (TNF-α), interleukin-1β(IL-1β) and interleukin-6(IL-6), and white matter injury causes microglia to become pro-inflammatory and release inflammatory mediators, which attract more immune cells to the damaged area, increasing the inflammatory response. Moreover, white matter damage also causes dysfunction of blood–brain barrier, allows peripheral immune cells and inflammatory factors to invade the brain further, and enhances microglia activation forming a vicious circle that intensifies neuroinflammation. And these factors collectively promote the neuroinflammatory environment and neurodegeneration changes of PD. Overall, these findings not only deepen our understanding of the complexity of PD, but also provide new targets for the development of therapeutic strategies focused on inflammation and immune regulation mechanisms. In summary, this review provided the theoretical basis for clarifying the pathogenesis of PD, summarized the association between white matter damage and the immune cells in the central and peripheral nervous systems, and then emphasized their potential specific mechanisms of achieving crosstalk with further aggravating the pathological process of PD.

Cotton SNARE complex component GhSYP121 regulates salicylic acid signaling during defense against Verticillium dahliae.

Syntaxin of plant (SYP) plays a crucial role in SNARE-mediated membrane trafficking during endocytic and secretory pathways, contributing to the regulation and execution of plant immunity against pathogens. Verticillium wilt is among the most destructive fungal diseases affecting cotton worldwide. However, information regarding SYP family genes in cotton is scarce. Through genome-wide identification and transcriptome profiling, we identified GhSYP121, a Qa SNARE gene in Gossypium hirsutum. GhSYP121 is notably induced by Verticillium dahliae, the causal agent of Verticillium wilt in cotton, and acts as a negative regulator of defense against V. dahliae. This is evidenced by the reduced resistance of GhSYP121-deficient cotton and the increased susceptibility of GhSYP121-overexpressing lines. Furthermore, the activation of the salicylic acid (SA) pathway by V. dahliae is inversely correlated with the expression level of GhSYP121. GhSYP121 interacts with its cognate SNARE component, GhSNAP33, which is required for the penetration resistance against V. dahliae in cotton. Collectively, GhSYP121, as a member of the cotton SNARE complex, is involved in regulating the SA pathway during plant defense against V. dahliae. This finding enhances our understanding of the potential role of GhSYP121 in these distinct pathways that contribute to plant defense against V. dahliae infection.

Hydrogel loaded with bone marrow stromal cell-derived exosomes promotes bone regeneration by inhibiting inflammatory responses and angiogenesis

BACKGROUND Bone healing is a complex process involving early inflammatory immune regulation, angiogenesis, osteogenic differentiation, and biomineralization. Fracture repair poses challenges for orthopedic surgeons, necessitating the search for efficient healing methods. AIM To investigate the underlying mechanism by which hydrogel-loaded exosomes derived from bone marrow mesenchymal stem cells (BMSCs) facilitate the process of fracture healing. METHODS Hydrogels and loaded BMSC-derived exosome (BMSC-exo) gels were characterized to validate their properties. In vitro evaluations were conducted to assess the impact of hydrogels on various stages of the healing process. Hydrogels could recruit macrophages and inhibit inflammatory responses, enhance of human umbilical vein endothelial cell angiogenesis, and promote the osteogenic differentiation of primary cranial osteoblasts. Furthermore, the effect of hydrogel on fracture healing was confirmed using a mouse fracture model. RESULTS The hydrogel effectively attenuated the inflammatory response during the initial repair stage and subsequently facilitated vascular migration, promoted the formation of large vessels, and enabled functional vascularization during bone repair. These effects were further validated in fracture models. CONCLUSION We successfully fabricated a hydrogel loaded with BMSC-exo that modulates macrophage polarization and angiogenesis to influence bone regeneration.

Mutations in the non-catalytic polyproline motif destabilize TREX1 and amplify cGAS-STING signaling.

The cGAS-STING pathway detects cytosolic DNA and activates a signaling cascade that results in a type I interferon (IFN) response. The endoplasmic reticulum (ER)-associated exonuclease TREX1 suppresses cGAS-STING by eliminating DNA from the cytosol. Mutations that compromise TREX1 function are linked to autoinflammatory disorders, including systemic lupus erythematosus (SLE) and Aicardi-Goutières syndrome (AGS). Despite key roles in regulating cGAS-STING and suppressing excessive inflammation, the impact of many disease-associated TREX1 mutations-particularly those outside of the core catalytic domains-remains poorly understood. Here, we characterize a recessive AGS-linked TREX1 P61Q mutation occurring within the poorly characterized polyproline helix (PPII) motif. In keeping with its position outside of the catalytic core or ER targeting motifs, neither the P61Q mutation, nor aggregate proline-to-alanine PPII mutation, disrupts TREX1 exonuclease activity, subcellular localization, or cGAS-STING regulation in overexpression systems. Introducing targeted mutations into the endogenous TREX1 locus revealed that PPII mutations destabilize the protein, resulting in impaired exonuclease activity and unrestrained cGAS-STING activation. Overall, these results demonstrate that TREX1 PPII mutations, including P61Q, impair proper immune regulation and lead to autoimmune disease through TREX1 destabilization.

Poly (I:C)-Induced microRNA-30b-5p Negatively Regulates the JAK/STAT Signaling Pathway to Mediate the Antiviral Immune Response in Silver Carp (Hypophthalmichthys molitrix) via Targeting CRFB5

In aquaculture, viral diseases pose a significant threat and can lead to substantial economic losses. The primary defense against viral invasion is the innate immune system, with interferons (IFNs) playing a crucial role in mediating the immune response. With advancements in molecular biology, the role of non-coding RNA (ncRNA), particularly microRNAs (miRNAs), in gene expression has gained increasing attention. While the function of miRNAs in regulating the host immune response has been extensively studied, research on their immunomodulatory effects in teleost fish, including silver carp (Hyphthalmichthys molitrix), is limited. Therefore, this research aimed to investigate the immunomodulatory role of microRNA-30b-5p (miR-30b-5p) in the antiviral immune response of silver carp (Hypophthalmichthys molitrix) by targeting cytokine receptor family B5 (CRFB5) via the JAK/STAT signaling pathway. In this study, silver carp were stimulated with polyinosinic-polycytidylic acid (poly (I:C)), resulting in the identification of an up-regulated miRNA (miR-30b-5p). Through a dual luciferase assay, it was demonstrated that CRFB5, a receptor shared by fish type I interferon, is a novel target of miR-30b-5p. Furthermore, it was found that miR-30b-5p can suppress post-transcriptional CRFB5 expression. Importantly, this study revealed for the first time that miR-30b-5p negatively regulates the JAK/STAT signaling pathway, thereby mediating the antiviral immune response in silver carp by targeting CRFB5 and maintaining immune system stability. These findings not only contribute to the understanding of how miRNAs act as negative feedback regulators in teleost fish antiviral immunity but also suggest their potential therapeutic measures to prevent an excessive immune response.

Chitinases: expanding the boundaries of knowledge beyond routinized chitin degradation.

Chitinases, enzymes that degrade chitin, have long been studied for their role in various biological processes. They play crucial roles in the moulting process of invertebrates, the digestion of chitinous food, and defense against chitin-bearing pathogens. Additionally, chitinases are involved in physiological functions in crustaceans, such as chitinous food digestion, moulting, and stress response. Moreover, chitinases are universally distributed in organisms from viruses to mammals and have diverse functions including tissue degradation and remodeling, nutrition uptake, pathogen invasion, and immune response regulation. The discovery of these diverse functions expands our understanding of the biological significance and potential applications of chitinases. However, recent research has shown that chitinases possess several other functions beyond just chitin degradation. Their potential as biopesticides, therapeutic agents, and tools for bioremediation underscores their significance in addressing global challenges. More importantly, we noted that they may be applied as bioweapons if ethical regulations regarding production, engineering and application are overlooked.

Dual effects of Psoraleae Fructus on the liver: hepatoprotection or hepatoxicity?

Psoraleae Fructus, the dried mature fruit of the leguminous plant Psoralea corylifolia L., contains flavonoids, coumarins, monoterpene phenols, and benzofurans. It exhibits various pharmacological activities, including immune regulation, antioxidant properties, photosensitivity, and estrogen-like effects, and finds extensive use in the clinical treatment of osteoporosis, vitiligo, and psoriasis. Extensive pharmacological research has demonstrated that Psoraleae Fructus and its components improve liver function and protect hepatocytes in animal and cellular models of liver diseases. Moreover, with the increasing clinical applications of Psoraleae Fructus and its derivatives, as well as the progression in adverse drug reaction surveillance, there is an increase in clinical cases involving these preparations and the enhancement of monitoring for any adverse reactions linked to Psoraleae Fructus and its related compounds. Here, we examined the hepatoprotective effects and hepatotoxicity of the monomer components, extracts, and related preparations of Psoraleae Fructus. We aim to contribute to safety evaluation, facilitate informed clinical application, and foster advancements in Psoraleae Fructus and its derivatives.

Celastrus orbiculatus Extract Inhibits Immune Inflammatory Thrombotic State of B-Lymphoma.

To investigate the inhibitory effect of Celastrus orbiculatus extracts (COE) on the proliferation of lymphoma cells and the immune regulation ability on inflammation and thrombophilia in vivo. The 38B9 lymphoma cells were treated with COE (160 µ g/mL) and CTX (25 µ mol/L). The apoptosis rate and cell cycle of each group were detected by flow cytometry. The secretion of inflammatory factors, including interleukin (IL)-6, IL-10, and tumor necrosis factor α (TNF-α), in cell supernatant was detected by enzyme-linked immunosorbent assay (ELISA). In vivo, BALB/c mice were subcutaneously injected with 38B9 lymphoma cells to establish lymphoma model. COE (3 mg·kg-1·d-1) and CTX (40 mg·kg-1·d-1) were administered to the model mice, respectively. The expression of plasma inflammatory factors (IL-6, IL-10 and TNF-α) and thrombus indexes, including D-dimer (D-D), von Willebrand factor (vWF) and tissue factor (TF), were detected by ELISA before tumor bearing (1 d), after tumor formation (14 d) and after intervention (21 d). PicoGreen dsDNA was used to detect the level of serum neutrophil extracellular traps (NETs). Flow cytometry was used to detect the expression of platelet activation marker calcium-dependent lectin-like receptor 2 (CLEC-2). The tumor growth and survival of mice were recorded. The 38B9 lymphoma cells were apoptotic after the intervention of COE and CTX. The ratio of G2-M phase cells decreased in COE intervented cells compared with the control cells (P<0.05), and S phase cells decreased in CTX intervented cells (P<0.05). Also, the secretion level of IL-6 was significantly reduced after COE or CTX intervention (P<0.05), and IL-10 was significantly increased (P<0.05). Furthermore, the tumor mass was reduced, and the median survival time was longer in COE and CTX intervented tumor-bearing mice than in non-intervented mice. The significantly lower levels of TNF-α, IL-6, NETs, TF, DD and CLEC-2, as well as higher IL-10 were observed in COE and CTX treatment mice in comparision with the control mice (P<0.05). COE has a mild and stable anti-tumor effect, which can reduce the secretion of inflammatory factors by lymphoma cells and regulate thrombophilic state caused by tumor inflammatory microenvironment.

TIGIT Stimulation Suppresses Autoimmune Uveitis by Inhibiting Th17 Cell Infiltration.

T cell immunoglobulin and ITIM domain (TIGIT) is an immune checkpoint molecule that suppresses T cell activation and promotes an immunosuppressive environment to suppress autoimmune diseases. However, the impact of a TIGIT agonist as a treatment for ocular autoimmune disease has not been investigated. We examined TIGIT expression on Th17 and Treg cells, the role of TIGIT on experimental autoimmune uveitis (EAU) and Th17 cells, and the impact of Treg generation following TIGIT stimulation. TIGIT stimulation at the onset of clinical symptoms reduced the severity of uveitis and suppressed infiltration of Th17 cells into the eye. Further, Tregs from mice treated with the TIGIT agonist were capable of suppressing EAU in recipient mice. This report demonstrates that stimulation of TIGIT at onset of disease suppresses symptoms and allows for induction of regulatory immunity that provides resistance to uveitis.

Prevention of cyclophosphamide-induced immune suppression by polysaccharides from Apocynum venetum flowers via enhancing immune response, reducing oxidative stress, and regulating gut microbiota in mice

IntroductionEmerging proof suggests that Apocynum venetum flowers polysaccharide (AVFP) has immunomodulatory effects in vitro. However, the action mechanism of AVFA is still unclear in vivo. The purpose of this study is to probe into the potential mechanism of AVFA in immunosuppressed mice by investigating organ index, cytokine levels, anti-oxidative stress capacity, transcriptomics, and gut microbiota.MethodsImmunocompromised mice induced by cyclophosphamide (CTX) were divided into six groups. The enzyme-labeled method, hematoxylin and eosin, transcriptomics, and high-throughput sequencing were used to detect the regulatory effects of AVFP on immunocompromised mice and the function of AVFP on the concentration of short-chain fatty acids (SCFAs) by high-performance liquid chromatography (HPLC) analysis. The Spearman correlation analysis was used to analyze the correlation between the intestinal microbiota and biochemical indexes.ResultsThe experimental results illustrated that AVFP has protective effects against CTX-induced immunosuppression in mice by prominently increasing the organ index and levels of anti-inflammatory factors in serum in addition to enhancing the antioxidant capacity of the liver. Meanwhile, it could also signally decrease the level of pro-inflammatory cytokines in serum, the activity of transaminase in serum, and the content of free radicals in the liver, and alleviate the spleen tissue damage induced by CTX. Transcriptomics results discovered that AVFP could play a role in immune regulation by participating in the NF-κB signaling pathway and regulating the immune-related genes Bcl3, Hp, Lbp, Cebpd, Gstp2, and Lcn2. Gut microbiota results illustrated that AVFP could increase the abundance of beneficial bacteria, reduce the abundance of harmful bacteria, and regulate the metabolic function of intestinal microorganisms while dramatically improving the content of SCFAs, modulating immune responses, and improving the host metabolism. The Spearman analysis further evaluated the association between intestinal microbiota and immune-related indicators.ConclusionThese findings demonstrated that AVFP could enhance the immune effects of the immunosuppressed mice and improve the body’s ability to resist oxidative stress.

Agonistic anti-DCIR antibody inhibits ITAM-mediated inflammatory signaling and promotes immune resolution.

Dendritic cell inhibitory receptor (DCIR) is a C-type lectin receptor selectively expressed on myeloid cells, including monocytes, macrophage, dendritic cells, and neutrophils. Its role in immune regulation has been implicated in murine models and human genome-wide association studies (GWAS), suggesting defective DCIR function associates with increased susceptibility to autoimmune diseases such as rheumatoid arthritis, lupus and Sjogren's syndrome. However, little is known about the mechanisms underlying DCIR activation to dampen inflammation. Here, we developed anti-DCIR agonistic antibodies that promote phosphorylation on DCIR's immune receptor tyrosine-based inhibitory motifs (ITIM) and recruitment of SH2 containing protein tyrosine phosphatase-2 (SHP2) for reducing inflammation. We also explored the inflammation resolution by depleting DCIR+ cells with antibodies. Utilizing a human DCIR knock-in mouse model, we validated the anti-inflammatory properties of the agonistic anti-DCIR antibody in experimental peritonitis and colitis. These findings provide critical evidence for targeting DCIR to develop transformative therapies for inflammatory diseases.

#1116 Hyperuricemia worsens bacterial sepsis by suppressing neutrophil functions in CKD

Abstract Background and Aims Patients with kidney disease, especially those on dialysis, are more susceptible to infections such as peritonitis, sepsis, pneumonia, and are at a higher risk for infection-related mortality. Pathogenic mechanisms underlying the secondary immunodeficiency in kidney disease include gut dysbiosis and barrier dysfunction, persistent inflammation, immune paralysis due to increased levels of immunoregulatory metabolites (e.g. uric acid) and proteins (e.g. FGF23) [1]. Currently, it is unknown whether CKD-related hyperuricemia may contribute to the immune paralysis in this context. We hypothesized that hyperuricemia (HU) may aggravate the innate immune response to infection in CKD in mice. Method Mono- and polybacterial sepsis was induced by LPS injection or cecal ligation and puncture in Alb-creERT2;Glut9lox/lox mice with HU and/or CKD, and in Glut9lox/lox (healthy) control mice. After 24 hours, systemic inflammation was evaluated by measuring serum cytokine levels, immune cell activation and recruitment, and neutrophil extracellular trap release. Tissue injury in liver, heart, and kidney was assessed by performing RT-qPCR and immunohistochemistry. In addition, kidney function was determined by measuring the glomerular filtration rate (GFR). Additionally, mice were treated with urate-lowering therapy to reduce serum uric acid levels and the immune response and functional outcomes after sepsis is quantified. Results We found that both mono- and polybacterial sepsis caused systemic inflammation as indicated by an increased number of blood neutrophils (see Figure), neutrophil activation and pro-inflammatory cytokine levels as compared to the PBS-treated or sham-operated control groups in Glut9lox/lox healthy mice, respectively. Mice with sepsis also displayed a slightly worsened kidney function. Interestingly, HU significantly increased neutrophil numbers but decreased their activation status and the ability of neutrophils to form neutrophil extracellular traps in Alb-creERT2;Glut9lox/lox mice with sepsis as compared to the control groups, which was further aggravated in mice with CKD-related HU (CKD+HU). This impaired inflammatory response was partially reversible by lowering serum uric acid with febuxostat. Conclusion Our results identify hyperuricemia related or unrelated to kidney disease as immune regulator in bacterial infection by suppressing neutrophil functions in mice. Specifically targeting uric acid may help to overcome the secondary immunodeficiency related to kidney disease during infection but enhances sterile inflammation [2].