Pancreatic draining lymph nodes (PLNs) serve as a pathogenic hub contributing to the development of type 1 diabetes.

Type 1 diabetes (T1D) is a chronic, progressive autoinflammatory disorder resulting from the breakdown of self-tolerance and unrestrained ß cell-reactive immune response. Activation of immune cells is initiated in islet and amplified in lymphoid tissues, especially those pancreatic draining lymph nodes (PLNs). The knowledge of PLNs as the hub of aberrant immune response is continuously being replenished and renewed. Here we provide a PLN-centered view of T1D pathogenesis and emphasize that PLNs integrate signal inputs from the pancreas, gut, viral infection or peripheral circulation, undergo immune remodeling within the local microenvironment and export effector cell components into pancreas to affect T1D progression. In accordance, we suggest that T1D intervention can be implemented by three major ways: cutting off the signal inputs into PLNs (reduce inflammatory ß cell damage, enhance gut integrity and control pathogenic viral infections), modulating the immune activation status of PLNs and blocking the outputs of PLNs towards pancreatic islets. Given the dynamic and complex nature of T1D etiology, the corresponding intervention strategy is thus required to be comprehensive to ensure optimal therapeutic efficacy.

Saccharomyces boulardii protects against murine experimental colitis by reshaping the gut microbiome and its metabolic profile.

Introduction: Saccharomyces boulardii (S. boulardii) has shown clinical beneficial effect in inflammatory bowel diseases recently. However, the underlying mechanisms remain incompletely understood. The aim of present study was to tested whether S. boulardii targets gut microbiota to protect against the development of experimental colitis in mice. Methods: Female C57BL/6 mice were gavaged with S. boulardii for 3 weeks before being challenged with dextran sulphate sodium to induce ulcerative colitis. Bodyweight, diarrhea severity, intestinal permeability, colonic histopathology, colonic inflammatory status, and epithelial cell death of mice were examined. The fecal microbiota and its metabolomic profiles were detected by 16S rDNA sequencing and UPLC-MS, respectively. Results and Discussion: Supplementation with S. boulardii significantly prevented weight loss and colon shortening, lowered colonic inflammation, ameliorated epithelial injury, and enhanced the intestinal barrier integrity in colitis mice. By inhibiting the abundance of pathogenic bacteria and increasing the probiotics abundance, S. boulardii improved the microbial diversity and restored the microbiota dysbiosis. Moreover, it also modulated microbial metabolome and altered the relative contents of metabolites involving amino acids, lipids, energy and vitamin metabolisms. These yeast-driven shifts in gut flora and metabolites are were associated with each other and with the inflammation profile in colitis. Collectively, S. boulardii exerts protective effects on colitis in mice by reshaping gut microbiome and its metabolic profile, indicating it as a promising therapeutic avenue.

Removal of tetracycline in aqueous solution by iron-loaded biochar derived from polymeric ferric sulfate and bagasse.

In this study, the tetracycline (TC) removal performance of iron-loaded biochar (BPFSB) derived from sugarcane bagasse and polymerized iron sulfate was investigated, and the mechanism of TC removal was also explored by study of isotherms, kinetics and thermodynamics and characterization of fresh and used BPFSB (XRD, FTIR, SEM and XPS). The results showed that under optimized conditions (initial pH 2; BPFSB dosage 0.8 g·L-1; TC initial concentration 100 mg·L-1; Contact time 24 h; temperature 298 K), the removal efficiency of TC was as high as 99.03%. The isothermal removal of TC followed well the Langmuir, Freundlich, and Temkin models, indicating that multilayer surface chemisorption dominated the TC removal. The maximum removal capacity of TC by BPFSB at different temperatures was 185.5 mg·g-1 (298 K), 192.7 mg·g-1 (308 K), and 230.9 mg·g-1 (318 K), respectively. The pseudo-second-kinetic model described the TC removal better, while its rate-controlling step was a combination of liquid film diffusion, intraparticle diffusion, and chemical reaction. Meanwhile, TC removal was also a spontaneous and endothermic process, during which the randomness and disorder between the solid-liquid interface was increased. According to the characterization of BPFSBs before and after TC removal, H-bonding and complexation were the major interactions for TC surface adsorption. Furthermore, BPFSB was efficiently regenerated by NaOH. In summary, BPFSB had the potential for practical application in TC removal.

[Removal Performance and Mechanism of Potassium Permanganate Modified Coconut Shell Biochar for Cd(â ¡) and Ni(â ¡) in Aquatic Environment].

In this study, coconut shell biochar modified by KMnO4 (MCBC) was used as the adsorbent, and its removal performance and mechanism for Cd(Ⅱ) and Ni(Ⅱ) were discussed. When the initial pH and MCBC dosage were separately 5 and 3.0 g·L-1, respectively, the removal efficiencies of Cd(Ⅱ) and Ni(Ⅱ) were both higher than 99%. The removal of Cd(Ⅱ) and Ni(Ⅱ) was more in line with the pseudo-second-order kinetic model, indicating that their removal was dominated by chemisorption. The rate-controlling step for Cd(Ⅱ) and Ni(Ⅱ) removal was the fast removal stage, for which the rate depended on the liquid film diffusion and intraparticle diffusion (surface diffusion). Cd(Ⅱ) and Ni(Ⅱ) were mainly attached to the MCBC via surface adsorption and pore filling, in which the contribution of surface adsorption was greater. The maximum adsorption amounts of Cd(Ⅱ) and Ni(Ⅱ) by MCBC were individually 57.18 mg·g-1 and 23.29 mg·g-1, which were approximately 5.74 and 6.97 times that of the precursor (coconut shell biochar), respectively. The removal of Cd(Ⅱ) and Zn(Ⅱ) was spontaneous and endothermic and had obvious thermodynamic characteristics of chemisorption. Cd(Ⅱ) was attached to MCBC through ion exchange, co-precipitation, complexation reaction, and cation-π interaction, whereas Ni(Ⅱ) was removed by MCBC via ion exchange, co-precipitation, complexation reaction, and redox. Among them, co-precipitation and complexation were the main modes of surface adsorption of Cd(Ⅱ) and Ni(Ⅱ). Additionally, the proportion of amorphous Mn-O-Cd or Mn-O-Ni in the complex may have been higher. These research results will provide important technical support and theoretical basis for the practical application of commercial biochar in the treatment of heavy metal wastewater.

UBC9 deficiency enhances immunostimulatory macrophage activation and subsequent antitumor T cell response in prostate cancer.

The role of tumor-associated macrophages (TAMs), along with the regulatory mechanisms underlying distinct macrophage activation states, remains poorly understood in prostate cancer (PCa). Herein, we report that PCa growth in mice with macrophage-specific Ubc9 deficiency is substantially suppressed compared with that in wild-type littermates, an effect partially ascribed to the augmented CD8+ T cell response. Biochemical and molecular analyses revealed that signal transducer and activator of transcription 4 (STAT4) is a crucial UBC9-mediated SUMOylation target, with lysine residue 350 (K350) as the major modification site. Site-directed mutation of STAT4 (K350R) enhanced its nuclear translocation and stability, thereby facilitating the proinflammatory activation of macrophages. Importantly, administration of the UBC9 inhibitor 2-D08 promoted the antitumor effect of TAMs and increased the expression of PD-1 on CD8+ T cells, supporting a synergistic antitumor efficacy once it combined with the immune checkpoint blockade therapy. Together, our results demonstrate that ablation of UBC9 could reverse the immunosuppressive phenotype of TAMs by promoting STAT4-mediated macrophage activation and macrophage-CD8+ T cell crosstalk, which provides valuable insights to halt the pathogenic process of tumorigenesis.

Arginine metabolism regulates the pathogenesis of inflammatory bowel disease.

The pathogenesis of inflammatory bowel disease (IBD) is related to genetic susceptibility, enteric dysbiosis, and uncontrolled, chronic inflammatory responses that lead to colonic tissue damage and impaired intestinal absorption. As a consequence, patients with IBD are prone to nutrition deficits after each episode of disease resurgence. Nutritional supplementation, especially for protein components, is often implemented during the remission phase of IBD. Notably, ingested nutrients could affect the progression of IBD and the prognostic outcome of patients; therefore, they should be cautiously evaluated prior to being used for IBD intervention. Arginine (Arg) is a semi-essential amino acid required for protein synthesis and intimately associated with gut pathophysiology. To help optimize arginine-based nutritional intervention strategies, the present work summarizes that during the process of IBD, patients manifest colonic Arg deficiency and the turbulence of Arg metabolic pathways. The roles of Arg-nitric oxide (catalyzed by inducible nitric oxide synthase) and Arg-urea (catalyzed by arginases) pathways in IBD are debatable; the Arg-polyamine and Arg-creatine pathways are mainly protective. Overall, supplementation with Arg is a promising therapeutic strategy for IBD; however, the dosage of Arg may need to be carefully tailored for different individuals at different disease stages. Additionally, the combination of Arg supplementation with inhibitors of Arg metabolic pathways as well as other treatment options is worthy of further exploration.

Facile preparation of activated carbon supported nano zero-valent iron for Cd(â ¡) removal in aqueous environment.

Activated carbon-supported nano-zero-valent iron (nZVI@AC) is considered to be one of the most promising materials for in-situ remediation of pollutants in aqueous environment, while liquid phase reduction (LPR) is one of the most commonly used preparation methods for nZVI@AC. However, the complex operation and the requirement of various agents limit the practical application of the traditional liquid-phase reduction (TLPR). In this study, an improved liquid phase reduction method (ILPR) was proposed, which was characterized by solid-state dosing of reducing agents. Compared with TLPR, ILPR simplified the preparation process, while there was no requirement of polyethylene glycol and ethanol. When the Cd(II) removal efficiency was used as the evaluation index, the preferred parameters of ILPR were as follows: AC/FeSO4·7H2O mass ratio was 15:1; NaBH4 dosage was 8 g; ultrasonic time was 1 h; stirring time was 20 min. Moreover, the Cd(II) removal efficiency of nZVI@AC prepared by ILPR (nZVI@AC-I) was greater than 92.00%, which was superior to that of nZVI@AC prepared by TLPR (nZVI@AC-T). The characterization results showed that the pore parameters, surface functional groups and iron contents of nZVI@AC-I and nZVI@AC-T were basically the same. However, the distribution of iron-containing particles on the surface of nZVI@AC-I was more uniform. Furthermore, the Fe0 in nZVI@AC-I had a smaller particle size and a higher content. Overall, this study provided a promising approach for nZVI@AC preparation.

The interferon regulatory factors, a double-edged sword, in the pathogenesis of type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease resulted from the unrestrained inflammatory attack towards the insulin-producing islet ß cells. Although the exact etiology underlying T1D remains elusive, viral infections, especially those specific strains of enterovirus, are acknowledged as a critical environmental cue involved in the early phase of disease initiation. Viral infections could either directly impede ß cell function, or elicit pathological autoinflammatory reactions for ß cell killing. Autoimmune responses are bolstered by a massive body of virus-derived exogenous pathogen-associated molecular patterns (PAMPs) and the presence of ß cell-derived damage-associated molecular patterns (DAMPs). In particular, the nucleic acid components and the downstream nucleic acid sensing pathways serve as the major effector mechanism. The endogenous retroviral RNA, mitochondrial DNA (mtDNA) and genomic fragments generated by stressed or dying ß cells induce host responses reminiscent of viral infection, a phenomenon termed as viral mimicry during the early stage of T1D development. Given that the interferon regulatory factors (IRFs) are considered as hub transcription factors to modulate immune responses relevant to viral infection, we thus sought to summarize the critical role of IRFs in T1D pathogenesis. We discuss with focus for the impact of IRFs on the sensitivity of ß cells to cytokine stimulation, the vulnerability of ß cells to viral infection/mimicry, and the intensity of immune response. Together, targeting certain IRF members, alone or together with other therapeutics, could be a promising strategy against T1D.

Aloperine Ameliorates IMQ-Induced Psoriasis by Attenuating Th17 Differentiation and Facilitating Their Conversion to Treg.

Aloperine is an anti-inflammatory compound isolated from the Chinese herb Sophora alopecuroides L. Previously, our group has reported that the generation of induced Treg was promoted by aloperine treatment in a mouse colitis model. However, the effect of aloperine on effector T cell subsets remains unclear. We therefore carefully examined the effect of aloperine on the differentiation of major subsets of T helper cells. Based on our results, psoriasis, a Th17 dominant skin disease, is selected to explore the potential therapeutic effect of aloperine in vivo. Herein, we demonstrated that topical application of aloperine suppressed epidermal proliferation, erythema, and infiltration of inflammatory cells in skin lesions. Mechanistic studies revealed that aloperine suppressed the differentiation of Th17 cells directly through inhibiting the phosphorylation of STAT3 or indirectly through impairing the secretion of Th17-promoting cytokines by dendritic cells. Moreover, aloperine enhanced the conversion of Th17 into Treg via altering the pSTAT3/pSTAT5 ratio. Collectively, our study supported that aloperine possesses the capacity to affect Th17 differentiation and modulates Th17/Treg balance, thereby alleviating imiquimod (IMQ)-induced psoriasis in mice.

SUMOylation of PDPK1 Is required to maintain glycolysis-dependent CD4 T-cell homeostasis.

The immune system is finely tuned to fight against infections, eradicate neoplasms, and prevent autoimmunity. Protein posttranslational modification (PTM) constitutes a molecular layer of regulation to guarantee the proper intensity of immune response. Herein, we report that UBC9-mediated protein SUMOylation plays an essential role in peripheral CD4 T-cell proliferation, but without a perceptible impact on T-cell polarization. Both conventional T-cell (Tcon) and regulatory T-cell (Treg) maintenance are differentially affected, which was likely caused by a shared deficit in cell glycolytic metabolism. Mechanistically, PDPK1 (3-phosphoinositide-dependent protein-kinase 1) was identified as a novel SUMOylation substrate, which occurred predominantly at lysine 299 (K299) located within the protein-kinase domain. Loss of PDPK1 SUMOylation impeded its autophosphorylation at serine 241 (S241), thereby leading to hypoactivation of downstream mTORC1 signaling coupled with incompetence of cell proliferation. Altogether, our results revealed a novel regulatory mechanism in peripheral CD4 T-cell homeostatic proliferation, which involves SUMOylation regulation of PDPK1-mTORC1 signaling-mediated glycolytic process.

MBD2 acts as a repressor to maintain the homeostasis of the Th1 program in type 1 diabetes by regulating the STAT1-IFN-γ axis.

The methyl-CpG-binding domain 2 (MBD2) interprets DNA methylome-encoded information through binding to the methylated CpG DNA, by which it regulates target gene expression at the transcriptional level. Although derailed DNA methylation has long been recognized to trigger or promote autoimmune responses in type 1 diabetes (T1D), the exact role of MBD2 in T1D pathogenesis, however, remains poorly defined. Herein, we generated an Mbd2 knockout model in the NOD background and found that Mbd2 deficiency exacerbated the development of spontaneous T1D in NOD mice. Adoptive transfer of Mbd2-/- CD4 T cells into NOD.scid mice further confirmed the observation. Mechanistically, Th1 stimulation rendered the Stat1 promoter to undergo a DNA methylation turnover featured by the changes of DNA methylation levels or patterns along with the induction of MBD2 expression, which then bound to the methylated CpG DNA within the Stat1 promoter, by which MBD2 maintains the homeostasis of Th1 program to prevent autoimmunity. As a result, ectopic MBD2 expression alleviated CD4 T cell diabetogenicity following their adoptive transfer into NOD.scid mice. Collectively, our data suggest that MBD2 could be a viable target to develop epigenetic-based therapeutics against T1D in clinical settings.

Xiaoyao Pill Improves the Affective Dysregulation of Sleep-deprived Female Mice by Inhibiting Brain Injury and Regulating the Content of Monoamine Neurotransmitter.

BACKGROUND: Sleep curtailment is a serious problem in many societies. Clinical evidence has shown that sleep deprivation is associated with mood dysregulation, formation of false memory, cardio-metabolic risk factors and outcomes, inflammatory disease risk, and all-cause mortality. The affective disorder dysregulation caused by insufficient sleep has become an increasingly serious health problem. However, to date, not much attention has been paid to the mild affective dysregulation caused by insufficient sleep, and there is no clear and standard therapeutic method to treat it. The Xiaoyao Pill is a classic Chinese medicinal formula, with the effect of dispersing stagnated hepatoqi, invigorating the spleen, and nourishing the blood. Therefore, it is most commonly used to treat gynecological diseases in China. In the present study, the effects of the Xiaoyao Pill on affective dysregulation of sleep-deprived mice and its underlying molecular mechanisms were investigated. METHODS: Forty adult female mice were used in the present study. The sleep deprivation model was established by improving the multi-platform water environment method. After 7 consecutive days of sleep deprivation, the mice were administrated low (LXYP, 0.32mg/kg) and high (HXYP, 0.64 mg/kg) doses of the Xiaoyao Pill for two weeks. Then, the body weight, behavioral deficits, and histopathology were evaluated. Meanwhile, the expression of c-fos protein and the concentrations of monoamine neurotransmitters in the hippocampus and prefrontal cortex were determined after two weeks of treatment. RESULTS: Xiaoyao Pill treatment significantly increased body weight and sucrose consumption and decreased the irritability scores of the sleep-deprived mice. Meanwhile, Xiaoyao Pill treatment prevented brain injury and inhibited the expression of c-fos protein in the hippocampus and prefrontal cortex. In addition, HXYP treatment significantly upregulated the levels of NE in the hippocampus and prefrontal cortex (p < 0.01). LXYP treatment significantly up-regulated the levels of 5-HT in the prefrontal cortex. Meanwhile, both HXYP and LXYP treatment significantly upregulated the levels of DA in the prefrontal cortex (p < 0.05 or p < 0.01) of sleep-deprived mice. CONCLUSION: The present study demonstrates that Xiaoyao Pill treatment prevented the behavioral deficits of mice induced by sleep deprivation by promoting the recovery of brain tissue injury and up-regulating the levels of NE, 5-HT, and DA in the brain tissue.

Revisiting the Antigen-Presenting Function of ß Cells in T1D Pathogenesis.

Type 1 diabetes (T1D) is characterized by the unresolved autoimmune inflammation and islet ß cell destruction. The islet resident antigen-presenting cells (APCs) including dendritic cells and macrophages uptake and process the ß cell-derived antigens to prime the autoreactive diabetogenic T cells. Upon activation, those autoreactive T cells produce copious amount of IFN-γ, TNF-α and IL-1ß to induce ß cell stress and death. Autoimmune attack and ß cell damage intertwine together to push forward this self-destructive program, leading to T1D onset. However, ß cells are far beyond a passive participant during the course of T1D development. Herein in this review, we summarized how ß cells are actively involved in the initiation of autoimmune responses in T1D setting. Specifically, ß cells produce modified neoantigens under stressed condition, which is coupled with upregulated expression of MHC I/II and co-stimulatory molecules as well as other immune modules, that are essential properties normally exhibited by the professional APCs. At the cellular level, this subset of APC-like ß cells dynamically interacts with plasmacytoid dendritic cells (pDCs) and manifests potency to activate autoreactive CD4 and CD8 T cells, by which ß cells initiate early autoimmune responses predisposing to T1D development. Overall, the antigen-presenting function of ß cells helps to explain the tissue specificity of T1D and highlights the active roles of structural cells played in the pathogenesis of various immune related disorders.

The MAPK dual specific phosphatase (DUSP) proteins: A versatile wrestler in T cell functionality.

The functional state of T cells is diverse and under dynamic control for adapting to the changes of microenvironment. Reversible protein phosphorylation represents an important post-translational modification that not only involves in the immediate early response of T cells, but also affects their functionality in the long run. Perturbation of global phosphorylation profile and/or phosphorylation of specific signaling nodes result in aberrant T cell activity. Dual specific phosphatases (DUSPs), which target MAPKs and beyond, have increasingly been emerged as a versatile regulator in T cell biology. Herein in this mini review, we sought to summarize and discuss the impact of DUSP proteins on the regulation of effector T cell activity, T cell polarization, regulatory T cell development and T cell senescence/exhaustion. Given the distinctive engagement of each DUSP member under various disease settings such as chronic infection, autoimmune disorders, cancer and age-related diseases, DUSP proteins likely hold the promise to become a druggable target other than the existing therapeutics that are predominantly by manipulating protein kinase activity.

Efficient absorptive removal of Cd(â ¡) in aqueous solution by biochar derived from sewage sludge and calcium sulfate.

Biochar derived from co-pyrolysis of sewage sludge and calcium sulfate was used to remove Cd(II) from aqueous solution. The results showed that the Cd(Ⅱ) adsorption better followed Freundlich model, and the maximum adsorption capacities were 109.0 mg/g (288 K), 127.9 mg/g (298 K) and 145.4 mg/g (308 K). The Cd(Ⅱ) removal was a multi-layer adsorption process dominated by chemisorption, which was also a spontaneous and endothermic process. The contribution of physisorption gradually increased as the Cd(Ⅱ) initial concentration. The Cd(Ⅱ) removal process which better followed pseudo-second-order kinetic model, was divided into three stages. The first (0-0.3 h) and second stages (0.3-2 h) were separately controlled by liquid film diffusion/intraparticle diffusion/chemical reaction and liquid film diffusion/chemical reaction, while the third stage (0.3-24 h) was the dynamic equilibrium process. The speciation distribution of Cd on biochar surface was mainly CdCO3/CdOOC and CdO/CdSiO3, indicating coprecipitation, ion exchange and complexation contributed more to the Cd(Ⅱ) removal.

Targeted Inhibition of FTO Demethylase Protects Mice Against LPS-Induced Septic Shock by Suppressing NLRP3 Inflammasome.

Sepsis refers to the systemic inflammatory response syndrome caused by infection. It is a major clinical problem and cause of death for patients in intensive care units worldwide. The Fat mass and obesity-related protein (FTO) is the primary N6-methyladenosine demethylase. However, the role of FTO in the pathogenesis of inflammatory diseases remains unclear. We herein show that nanoparticle-mediated Fto-siRNA delivery or FTO inhibitor entacapone administration dramatically inhibited macrophage activation, reduced the tissue damage and improved survival in a mouse model of LPS-induced endotoxic shock. Importantly, ablation of FTO could inhibit NLRP3 inflammasome through FoxO1/NF-κB signaling in macrophages. In conclusion, FTO is involved in inflammatory response of LPS-induced septic shock and inhibition of FTO is promising for the treatment of septic shock.

The role of hydrogen sulphide signalling in macrophage activation.

Hydrogen sulphide (H2 S) is the latest identified small gaseous mediator enabled by its lipophilic nature to freely permeate the biological membranes. Initially, H2 S was recognized by its roles in neuronal activity and vascular relaxation, which makes it an important molecule involved in paracrine signalling pathways. Recently, the immune regulatory function of gasotransmitters, H2 S in particular, is increasingly being appreciated. Endogenous H2 S level has been linked to macrophage activation, polarization and inflammasome formation. Mechanistically, H2 S-induced protein S-sulphydration suppresses several inflammatory pathways including NF-κB and JNK signalling. Moreover, H2 S serves as a potent cellular redox regulator to modulate epigenetic alterations and to promote mitochondrial biogenesis in macrophages. Here in this review, we intend to summarize the recent advancements of H2 S studies in macrophages, and to discuss with focus on the therapeutic potential of H2 S donors by targeting macrophages. The feasibility of H2 S signalling component as a macrophage biomarker under disease conditions would be also discussed.

The AHR Signaling Attenuates Autoimmune Responses During the Development of Type 1 Diabetes.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcriptional factor widely expressed in immune cells. Its ligands range from xenobiotics and natural substances to metabolites, which renders it capable of sensing and responding to a variety of environmental cues. Although AHR signaling has long been recognized to be implicated in the pathogenesis of autoimmune disorders, such as rheumatoid arthritis (RA), colitis, and systemic lupus erythematosus (SLE), its effect on the pathogenesis of type 1 diabetes (T1D) remains less understood. In this review, we intend to summarize its potential implication in T1D pathogenesis and to sort out the related regulatory mechanisms in different types of immune cells. Emerging evidence supports that ß cell destruction caused by autoimmune responses can be rectified by AHR signaling. Upon activation by its ligands, AHR not only modulates the development and functionality of immune cells, but also suppresses the expression of inflammatory cytokines, through which AHR attenuates autoimmune responses during the course of T1D development. Since AHR-initiated biological effects vary between different types of ligands, additional studies would be necessary to characterize or de novo synthesize effective and safe ligands aimed to replenish our arsenal in fighting autoimmune responses and ß mass loss in a T1D setting.

Loss of ubiquitin-conjugating enzyme E2 (Ubc9) in macrophages exacerbates multiple low-dose streptozotocin-induced diabetes by attenuating M2 macrophage polarization.

Type 1 diabetes (T1D) is characterized by the selective autoimmune destruction of the islet ß cells, and macrophages play a significant role in this process. Small ubiquitin-like modification (SUMOylation) is an important posttranslational modification involved in T1D pathogenesis, but its function in macrophages remains unexplored. We presently developed and used macrophage-specific ubiquitin-conjugating enzyme E2 (Ubc9) knockout (LyzM-Cre-Ubc9fl/fl, KO) mice to address the impact of SUMOylation on macrophage function in a T1D model. We observed that blocking Ubc9 in macrophages exacerbated multiple-low dose streptozotocin (MLD-STZ)-induced diabetes. Specifically, after STZ treatment, blood glucose levels were consistently elevated in the KO mice. The KO mice exhibited a higher diabetes incidence than WT controls (85% vs. 55%, P < 0.01) along with a higher insulitis severity. The loss of Ubc9 impaired macrophage energy metabolism and attenuated macrophage M2 program, thereby enhancing T cell activation. Pancreas-resident macrophages, rather than migrant macrophages, played a predominant role in MLD-STZ-induced diabetes. Mechanistically, Ubc9-mediated SUMOylation of interferon regulator factor 4 (IRF4) enhanced its nuclear localization and stability, thereby transcribing IL-4 and arginase 1 (Arg1) to promote the macrophage M2 program. Ubc9-mediated SUMOylation modulates T1D risk at least in part by regulating macrophage function. Modulation of disturbed SUMOylation process in macrophages, either through cell adoptive transfer or targeted drug-delivery, could help to establish a tolerant pancreatic microenvironment and promote inflammation resolution in early insulitis stage, thus hindering T1D progression.

Ubc9 deficiency selectively impairs the functionality of common lymphoid progenitors (CLPs) during bone marrow hematopoiesis.

Hematopoietic development occurs in the bone marrow, and this process begins with hematopoietic stem cells (HSCs). Ubc9 is a unique E2-conjugating enzyme required for SUMOylation, an evolutionarily conserved post-translational modification system. We herein show that a conditional Ubc9 deletion in the hematopoietic system caused decreased thymus weight and reduced lymphocyte to myeloid cell ratio. Importantly, Ubc9 deletion in the hematopoietic system only selectively impaired the development of common lymphoid progenitors (CLPs) in the bone marrow and perturbed their potential to differentiate into lymphocytes, thereby decreasing the number of T/B cells in the periphery. Ubc9 was found to be required for CLP viability, and therefore, Ubc9 deficiency rendered CLPs to undergo apoptosis and attenuated their proliferation. Thus, Ubc9 plays a critical role in the regulation of CLP function during hematopoietic development in the bone marrow.