Altered TLR7 Expression-Mediated Immune Modulation Is Supportive of Persistent Replication and Intrauterine Transmission of HBV.

Hepatitis B Virus (HBV) is posing as a serious public health threat mainly due to its asymptomatic nature of infection in pregnancy and vertical transmission. Viral sensing toll-like receptors (TLR) and Interleukins (IL) are important molecules in providing an antiviral state. The study aimed to assess the role of TLR7-mediated immune modulation, which might have an impact in the intrauterine transmission of HBV leading to mother to child transmission of the virus. We investigated the expression pattern of TLR7, IL-3, and IL-6 by RT-PCR in the placentas of HBV-infected pregnant women to see their role in the intrauterine transmission of HBV. We further validated the expression of TLR7 in placentas using Immunohistochemistry. Expression analysis by RT-PCR of TLR7 revealed significant downregulation among the Cord blood (CB) HBV DNA positive and negative cases with mean ± standard deviation (SD) of 0.43 ± 0.22 (28) and 1.14 ± 0.57 (44) with p = 0.001. IL-3 and IL-6 expression revealed significant upregulation in the CB HBV DNA-positive cases with p = 0.001. Multinomial logistic regression analysis revealed that TLR7 and IL-3 fold change and mother HBeAg status are important predictors for HBV mother to child transmission. Immunohistochemistry revealed the decreased expression of TLR7 in CB HBV DNA-positive cases. This study reveals that the downregulation of TLR7 in the placenta along with CB HBV DNA-positive status may lead to intrauterine transmission of HBV, which may lead to vertical transmission of HBV.

EP300-ZNF384 transactivates IL3RA to promote the progression of B-cell acute lymphoblastic leukemia.

The EP300-ZNF384 fusion gene is an oncogenic driver in B-cell acute lymphoblastic leukemia (B-ALL). In the present study, we demonstrated that EP300-ZNF384 substantially induces the transcription of IL3RA and the expression of IL3Rα (CD123) on B-ALL cell membranes. Interleukin 3 (IL-3) supplementation promotes the proliferation of EP300-ZNF348-positive B-ALL cells by activating STAT5. Conditional knockdown of IL3RA in EP300-ZF384-positive cells inhibited the proliferation in vitro, and induced a significant increase in overall survival of mice, which is attributed to impaired propagation ability of leukemia cells. Mechanistically, the EP300-ZNF384 fusion protein transactivates the promoter activity of IL3RA by binding to an A-rich sequence localized at -222/-234 of IL3RA. Furthermore, forced EP300-ZNF384 expression induces the expression of IL3Rα on cell membranes and the secretion of IL-3 in CD19-positive B precursor cells derived from healthy individuals. Doxorubicin displayed a selective killing of EP300-ZNF384-positive B-ALL cells in vitro and in vivo. Collectively, we identify IL3RA as a direct downstream target of EP300-ZNF384, suggesting CD123 is a potent biomarker for EP300-ZNF384-driven B-ALL. Targeting CD123 may be a novel therapeutic approach to EP300-ZNF384-positive patients, alternative or, more likely, complementary to standard chemotherapy regimen in clinical setting.

Interleukin 3 Inhibits Glutamate-Cytotoxicity in Neuroblastoma Cell Line.

Interleukin 3 (IL-3) is a well-known pleiotropic cytokine that regulates the proliferation and differentiation of hematopoietic progenitor cells, triggering classical signaling pathways such as JAK/STAT, Ras/MAPK, and PI3K/Akt to carry out its functions. Interestingly, the IL-3 receptor is also expressed in non-hematopoietic cells, playing a crucial role in cell survival. Our previous research demonstrated the expression of the IL-3 receptor in neuron cells and its protective role in neurodegeneration. Glutamate, a principal neurotransmitter in the central nervous system, can induce cellular stress and lead to neurotoxicity when its extracellular concentrations surpass normal levels. This excessive glutamate presence is frequently observed in various neurological diseases. In this study, we uncover the protective role of IL-3 as an inhibitor of glutamate-induced cell death, analyzing the cytokine's signaling pathways during its protective effect. Specifically, we examined the relevance of JAK/STAT, Ras/MAPK, and PI3 K signaling pathways in the molecular mechanism triggered by IL-3. Our results show that the inhibition of JAK, ERK, and PI3 K signaling pathways, using pharmacological inhibitors, effectively blocked IL-3's protective role against glutamate-induced cell death. Additionally, our findings suggest that Bcl-2 and Bax proteins may be involved in the molecular mechanism triggered by IL-3. Our investigation into IL-3's ability to protect neuronal cells from glutamate-induced damage offers a promising therapeutic avenue with potential clinical implications for several neurological diseases characterized by glutamate neurotoxicity.

Ginsenoside RH4 inhibits Ang II-induced myocardial remodeling by interfering with NFIL3.

Ventricular remodeling refers to the structural and functional changes of the heart under various stimuli or disease influences and may also be accompanied by myocardial fibrosis, where an excessive amount of fibrous tissue appears in the myocardial tissue, affecting the heart's normal contraction and relaxation. Hypertension is posing the potential risk of causing myocardial injury and remodeling. The significance of the renin-angiotensin-aldosterone system (RAAS) in myocardial remodeling cannot be overlooked. Drug targeting of RAAS can effectively lower blood pressure and reduce left ventricular mass. Studies have shown that ginsenoside Rh4 can inhibit oxidative stress and inflammatory responses. In this study, a myocardial remodeling model was established using angiotensin (Ang) II, and the inhibitory effect of RH4 on myocardial hypertrophy and remodeling induced by Ang II was investigated using pathological staining and quantitative polymerase chain reaction (qPCR). Immunofluorescence and qPCR demonstrated that Rh4 causes myocardial hypertrophy and the generation of reactive oxygen species (ROS) in vitro. The Rh4 target was identified using transcriptomics. The findings indicated that RH4 could inhibit myocardial hypertrophy, inflammatory fibrosis, and oxidative stress induced by Ang II, suggesting potential cardiovascular protection effects. In vitro experiments have shown that Rh4 inhibits myocardial hypertrophy. Transcriptomics revealed that nuclear factor interleukin-3 (NFIL3) is a downstream regulator of Rh4. By constructing AAV9-NFIL3 and injecting it into mice, it was found that NFIL3 overexpression interfered with anti-Ang II-induced myocardial remodeling of Rh4. These results indicate that Rh4 demonstrates potential therapeutic effects on myocardial hypertrophy and fibrosis.

NFIL3 contributes to cytotoxic T lymphocyte-mediated killing.

Cytotoxic T lymphocytes (CTLs) are key effectors of the adaptive immune system that recognize and eliminate virally infected and cancerous cells. In naive CD8+ T cells, T-cell receptor (TCR) engagement drives a number of transcriptional, translational and proliferation changes over the course of hours and days leading to differentiation into CTLs. To gain a better insight into this mechanism, we compared the transcriptional profiles of naive CD8+ T cells to those of activated CTLs. To find new regulators of CTL function, we performed a selective clustered regularly interspaced short palindromic repeats (CRISPR) screen on upregulated genes and identified nuclear factor IL-3 (NFIL3) as a potential regulator of cytotoxicity. Although NFIL3 has established roles in several immune cells including natural killer, Treg, dendritic and CD4+ T cells, its function in CD8+ CTLs is less well understood. Using CRISPR/Cas9 editing, we found that removing NFIL3 in CTLs resulted in a marked decrease in cytotoxicity. We found that in CTLs lacking NFIL3 TCR-induced extracellular signal-regulated kinase phosphorylation, immune synapse formation and granule release were all intact while cytotoxicity was functionally impaired in vitro. Strikingly, NFIL3 controls the production of cytolytic proteins as well as effector cytokines. Thus, NFIL3 plays a cell intrinsic role in modulating cytolytic mechanisms in CTLs.

TRPV1 Channel in Human Eosinophils: Functional Expression and Inflammatory Modulation.

The transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel expressed on sensory neurons and immune cells. We hypothesize that TRPV1 plays a role in human eosinophil function and is modulated by inflammatory conditions. TRPV1 expression on human eosinophils was examined by qPCR, flow cytometry, and immunohistochemistry, respectively. TRPV1 functionality was analyzed by investigating calcium flux, apoptosis, modulation by cytokines and acidic pH, and CD69 externalization using flow cytometry. Activation of TRPV1 induced calcium influx and prolonged survival. Although eosinophils were not directly activated by TRPV1 agonists, activation by IL-3 or GM-CSF was mainly restricted to TRPV1-positive eosinophils. TRPV1 surface content was increased by acidic pH, IL-3, IL-31, IL-33, TSLP, TNF-α, BDNF, and NGF-ß. Interestingly, TRPV1 was also expressed by eosinophils located in proximity to peripheral nerves in atopic dermatitis (AD) skin. In conclusion, eosinophils express functional TRPV1 channels which are increased by extracellular acidification and AD-related cytokines. Since eosinophils also express TRPV1 in AD skin, our results indicate an important role of TRPV1 for neuroimmune interaction mechanisms in itchy, inflammatory skin diseases, like AD.

Recent Advances in the Biology and CD123-Directed Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive myeloid malignancy of the dendritic cell lineage that affects patients of all ages, though the incidence appears to be highest in patients over the age of 60 years. Diagnosis is based on the presence of plasmacytoid dendritic cell precursors expressing CD123, the interleukin-3 (IL-3) receptor alpha, and a distinct histologic appearance. Timely diagnosis remains a challenge, due to lack of disease awareness and overlapping biologic and clinical features with other hematologic malignancies. Prognosis is poor with a median overall survival of 8 to 14 months, irrespective of disease presentation pattern. Historically, the principal treatment was remission induction therapy followed by a stem cell transplant (SCT) in eligible patients. However, bridging to SCT is often not achieved with induction chemotherapy regimens. The discovery that CD123 is universally expressed in BPDCN and is considered to have a pathogenetic role in its development paved the way for the successful introduction of tagraxofusp, a recombinant human IL-3 fused to a truncated diphtheria toxin payload, as an initial treatment for BPDCN. Tagraxofusp was approved in 2018 by the United States Food and Drug Administration for the treatment of patients aged 2 years and older with newly diagnosed and relapsed/refractory BPDCN, and by the European Medicines Agency in 2021 for first-line treatment of adults. The advent of tagraxofusp has opened a new era of precision oncology in the treatment of BPDCN. Herein, we present an overview of BPDCN biology, its diagnosis, and treatment options, illustrated by clinical cases.

Sequential engagement of adhesion molecules and cytokine receptors impacts both piecemeal and anaphylactic degranulation of human basophils.

Basophils are rare granulocytes in circulation which home to tissues in a process depending on rolling, adhesion and cytokine exposure. However, it is still unclear how these steps affect basophil degranulation. Our aim was to imitate these processes associated with homing by sequential crosslinking of adhesion molecules and cytokine exposure and evaluate the effect on basophil piecemeal (PMD) and anaphylactic degranulation (AND). Blood donors with or without allergic asthma were recruited from an ongoing cohort study. Basophils were subjected to CD62L-, CD49d- or CD11b crosslinking and IL-3 or IL-33 stimulation in different orders followed by anti-IgE and fMLP stimulation. Basophil CD203c and CD63 expression were analysed by flow cytometry to determine PMD and AND, respectively. IL-3 induced PMD in basophils and combined with CD62L- or CD11b crosslinking, IL-3 potentiated the degranulation regardless of sequential order. IL-3 priming followed by adhesion molecule crosslinking induced AND and potentiated the effect of anti-IgE. CD62L- and CD11b crosslinking did not further potentiate this effect. CD49d crosslinking followed by IL-3 increased CD63 expression following anti-IgE. IL-3 potentiated the effect of fMLP on AND while adhesion molecule crosslinking did not. IL-33 had impact on PMD only when followed by adhesion molecule crosslinking but did not potentiate neither IgE-dependent nor IgE-independent degranulation. Our data indicate that sequential interactions between basophils, cytokines and adhesion molecule ligands have a decisive effect on basophil degranulation and that these interactions are operational for fine-tuning the activity of tissue dwelling basophils. These data should be considered when the effect of different pharmaceutical on basophil function is studied.

The transcription factor NFIL3/E4BP4 regulates the developmental stage-specific acquisition of basophil function.

BACKGROUND: Basophils are rare but important effector cells in many allergic disorders. Contrary to their early progenitors, the terminal developmental processes of basophils in which they gain their unique functional properties are unknown. OBJECTIVE: We sought to identify a novel late-stage basophil precursor and a transcription factor regulating the terminal maturation of basophils. METHODS: Using flow cytometry, transcriptome analysis, and functional assays, we investigated the identification and functionality of the basophil precursors as well as basophil development. We generated mice with basophil-specific deletion of nuclear factor IL-3 (NFIL3)/E4BP4 and analyzed the functional impairment of NFIL3/E4BP4-deficient basophils in vitro and in vivo using an oxazolone-induced murine model of allergic dermatitis. RESULTS: We report a new mitotic transitional basophil precursor population (referred to as transitional basophils) that expresses the FcεRIα chain at higher levels than mature basophils. Transitional basophils are less responsive to IgE-linked degranulation but produce more cytokines in response to IL-3, IL-33, or IgE cross-linking than mature basophils. In particular, we found that the expression of NFIL3/E4BP4 gradually rises as cells mature from the basophil progenitor stage. Basophil-specific deletion of NFIL3/E4BP4 reduces the expression of genes necessary for basophil function and impairs IgE receptor signaling, cytokine secretion, and degranulation in the context of murine atopic dermatitis. CONCLUSIONS: We discovered transitional basophils, a novel late-stage mitotic basophil precursor cell population that exists between basophil progenitors and postmitotic mature basophils. We demonstrated that NFIL3/E4BP4 augments the IgE-mediated functions of basophils, pointing to a potential therapeutic regulator for allergic diseases.

Air pollution exposure is associated with rhinitis in older US adults via specific immune mechanisms.

BACKGROUND: Pathophysiology of rhinitis in older adults is largely unknown. We tested whether air pollution is associated with this condition and how immune mechanisms may play a role in this relationship. METHODS: We analyzed cross-sectional data from the National Social Life, Health, and Aging Project, a nationally representative study of older adults born between 1920 and 1947. Particulate matter ≤2.5 µm (PM2.5 ) air pollution exposure estimates were generated using validated spatiotemporal models. Presence of rhinitis was defined based on medication use (≥1: intranasal medications: steroids, antihistamines, lubricants, and/or decongestants, and/or oral medications: antihistamines and/or decongestants). K-means cluster analysis (Jaccard method) was used to group 13 peripheral blood cytokines into 3 clusters to facilitate functional determination. We fitted multivariate logistic regressions to correlate PM2.5 exposure with presence of rhinitis, controlling for confounders, and then determined the role of cytokines in this relationship. RESULTS: Long- (but not short-) term exposure to PM2.5 was associated with presence of rhinitis: 3-year exposure window, odds ratio (OR) = 1.32, 95% confidence interval (CI): 0.98, 1.80, per 1 standard deviation (SD) PM2.5 increase. Inclusion of cytokine cluster in the model led to a modestly stronger effect of PM2.5 exposure on rhinitis (OR = 1.37; 95% CI: 1.00, 1.87; 3-year exposure window). The particular immune profile responsible for this result was composed of elevated IL-3, IL-12, and IFN-γ (OR = 4.86, 95% CI: 1.10, 21.58, immune profile-PM2.5 exposure interaction term). CONCLUSION: We show for the first time that IL-3, IL-12, and IFN-γ explain in part the relationship between PM2.5 exposure and rhinitis in older US adults. If confirmed, these immune pathways may be used as therapeutic targets.

A Potential Role of NFIL3 in Atherosclerosis.

Nuclear factor interleukin-3 (NFIL3), a proline- and acidic-residue-rich (PAR) bZIP transcription factor, is called the E4 binding protein 4 (E4BP4) as well, which is relevant to regulate the circadian rhythms and the viability of cells. More and more evidence has shown that NFIL3 is associated with different cardiovascular diseases. In recent years, it has been found that NFIL3 has significant functions in the progression of atherosclerosis (AS) via the regulation of inflammatory response, macrophage polarization, some immune cells and lipid metabolism. In this overview, we sum up the function of NFIL3 during the development of AS and offer meaningful views how to treat cardiovascular disease related to AS.

Syndecan-1 as the Effect or Effector of the Endothelial Inflammatory Response?

INTRODUCTION: Syndecan-1 is a heparan sulfate proteoglycan found in the glycocalyx of vascular endothelial cells. Serum levels of syndecan-1 have repeatedly been demonstrated to increase following traumatic injury and shock, but it is unclear whether syndecan-1 plays an active role in the inflammatory response or is simply a biomarker of a state of hypoperfusion. The aim of this study was to identify the role of syndecan-1 role in the inflammatory process in the absence of trauma. METHODS: Male mice were randomized into five groups (n = 3). Four groups received increasing concentrations of syndecan-1 (1, 10, 100, and 1000pg/mL per blood volume) and a fifth group was given normal saline as a control via intravenous injection. These concentrations were selected based on previous syndecan-1 enzyme-linked immunosorbent assay data acquired following induced hemorrhagic shock in mice resulting in serum levels of 10-6000 pg/mL. Mice from each group were sacrificed at 1-, 4-, and 24-h time points for serum biomarker evaluation. A multiplex enzyme-linked immunosorbent assay was performed to analyze proinflammatory cytokines and chemokines including interleukin (IL)-1a, IL-1b, IL-2, IL-3, IL-4, IL-6, IL-10, IL-12, IL-17, monocyte chemoattractant protein-1, TNF-α, macrophage inflammatory protein-1α, granulocyte-macrophage colony-stimulating factor, and normal T cell expressed and presumably secreted levels. Whole blood was analyzed via rotational thromboelastometry in a separate group of mice dosed with syndecan-1 at 1000 pg/mL and compared to sham mice at 1 h. RESULTS: Tumor necrosis factor-α was significantly elevated in the 1000 pg/mL group compared to sham animals. There were no significant changes in IL-1a, IL-1b, IL-2, IL-3, IL-4, IL-6, IL-10, IL-12, monocyte chemoattractant protein--1, macrophage inflammatory protein-1α, granulocyte-macrophage colony-stimulating factor, or normal T cell expressed and presumably secretedat 1, 4, and 24 h for any group when compared to mice receiving saline alone. No significant differences were noted in coagulability between the 1000 pg/mL syndecan-1 group and shams at 1 h CONCLUSIONS: Inflammatory cytokine concentrations did not change with increasing dosage of syndecan-1 within mice at any timepoint, except for an acute change in tumor necrosis factor-α which was transient. Based on our results, syndecan-1 appears to be a biomarker for inflammation rather than an active participant in eliciting an inflammatory response. Further research will focus on the role of syndecan-1 following hemorrhagic shock.

Distinct roles of hematopoietic cytokines in the regulation of leukemia stem cells in murine MLL-AF9 leukemia.

Lymphoid-primed multipotent progenitor (LMPP)-like and granulocyte-monocyte progenitor (GMP)-like leukemia stem cells (LSCs) co-exist in the blood of most patients with acute myeloid leukemia (AML). Complete elimination of both types of LSCs is required to cure AML. Using an MLL-AF9-induced murine AML model, we studied the role of hematopoietic cytokines in the survival of LMPP- and GMP-like LSCs. We found that SCF or FLT3L promotes the survival of LMPP-like LSCs by stimulating Stat5-mediated Mcl1 expression, whereas interleukin-3 (IL-3) or IL-6 induces the survival of GMP-like LSCs by stimulating Stat3/nuclear factor κB (NF-κB)-mediated Bcl2 expression. Functional study demonstrated that, compared to AML cells cultured in IL-3 and IL-6 medium, AML cells in SCF- or Flt3L-only culture are highly clonogenic in in vitro culture and are highly leukemogenic in vivo. Our study suggests that co-inhibition of both STAT5-MCL1 and STAT3/NF-κB-BCL2 signaling might represent an improved treatment strategy against AML, specifically AML cases with a monocytic phenotype and/or FLT3 mutations.

Hematopoietic colony-stimulating factors in head and neck cancers: Recent advances and therapeutic challenges.

Colony-stimulating factors (CSFs) are key cytokines responsible for the production, maturation, and mobilization of the granulocytic and macrophage lineages from the bone marrow, which have been gaining attention for playing pro- and/or anti-tumorigenic roles in cancer. Head and neck cancers (HNCs) represent a group of heterogeneous neoplasms with high morbidity and mortality worldwide. Treatment for HNCs is still limited even with the advancements in cancer immunotherapy. Novel treatments for patients with recurrent and metastatic HNCs are urgently needed. This article provides an in-depth review of the role of hematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and interleukin-3 (IL-3; also known as multi-CSF) in the HNCs tumor microenvironment. We have reviewed current results from clinical trials using CSFs as adjuvant therapy to treat HNCs patients, and also clinical findings reported to date on the therapeutic application of CSFs toxicities arising from chemoradiotherapy.

NFIL3 aggravates human coronary artery endothelial cell injury by promoting ITGAM transcription in Kawasaki disease.

OBJECTIVE: High expression of nuclear factor interleukin-3 (NFIL3) and integrin Alpha M (ITGAM) was found in serum samples from Kawasaki disease (KD) patients through bioinformatics analysis. Hence, this study aimed to explore the biological functions of NFIL3 and ITGAM in KD serum-stimulated human coronary artery endothelial cells (HCAECs). METHODS: The differentially-expressed genes in KD were analyzed through bioinformatics analysis. Serum samples were obtained from 18 KD patients and 18 healthy volunteers, followed by detection of NFIL3 and ITGAM levels in KD serum. After HCAECs were transfected with sh-NFIL3, sh-ITGAM, or sh-NFIL3 + oe-ITGAM and underwent 24-h KD serum stimulation, cell viability and apoptosis and the levels of inflammation-related factors were measured. The binding between NFIL3 and ITGAM was validated by dual-luciferase and chromatin immunoprecipitation (ChIP) assays. RESULTS: NFIL3 and ITGAM were up-regulated in serum from KD patients and KD serum-stimulated HCAECs. Down-regulation of NFIL3 or ITGAM inhibited KD serum-induced cell apoptosis and inflammatory response of HCAECs and promoted cell viability. Mechanistically, NFIL3 promoted ITGAM transcription level. Up-regulation of ITGAM reversed the improvement of NFIL3 down-regulation on KD serum-induced HCAEC injury. CONCLUSION: NFIL3 aggravated KD serum-induced HCAEC injury by promoting ITGAM transcription, which provided new insights into the treatment of KD.

Association of granulocyte macrophage colony-stimulating factor and interleukin-17 levels with obsessive-compulsive disorder: a case-control study findings.

Obsessive-compulsive disorder (OCD) is a mental condition that affects many people and is characterized by recurring obsessions and compulsions. It significantly impacts individuals' ability to function ordinarily daily, affecting people of all ages. This study aimed to investigate whether or not the cytokines granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-17 (IL-17) are involved in the pathophysiology of OCD. A case-control study with 50 OCD patients and 38 healthy volunteers served as the controls for this investigation. The levels of GM-CSF and IL-17 in the serum of both groups were measured with enzyme-linked immunosorbent assay (ELISA) kits. In addition, the sociodemographic characteristics of the population under study were studied. Based on the findings of this study, OCD patients had significantly elevated levels of IL-17 than the controls, it appears that there may be a function for IL-17 in the pathophysiology of OCD. It was also discovered that the severity of OCD and IL-17 levels had a significant positive correlation. On the other hand, when comparing the levels of GM-CSF, there was no significant difference between the patients and the controls. This study provides evidence supporting the involvement of cytokine IL-17 in the pathophysiology of OCD. This study suggests IL-17 as a diagnostic biomarker for OCD and adds to our knowledge of the function that the immune system plays in this condition.

Altered IL-3 and lipocalin-2 levels are associated with the pathophysiology of major depressive disorder: a case-control study.

BACKGROUND: Major Depressive Disorder (MDD) is a common mental ailment and is the primary reason for disability. It manifests a severe impact on moods, thoughts, and physical health. At present, this disorder has become a concern in the field of public health. Alteration of neurochemicals is thought to be involved in the pathogenesis of many psychiatric disorders. Therefore, we aimed to evaluate serum IL-3 and lipocalin-2 in MDD patients and healthy controls (HCs). METHOD: We included a total of 376 participants in this study. Among them, 196 were MDD patients, and 180 were age-sex-matched HCs. MDD patients were recruited from the Psychiatry Department of Bangabandhu Sheikh Mujib Medical University (BSMMU), but the controls were from different parts of Dhaka. All study participants were evaluated by a psychiatrist using the DSM-5 criteria. To assess the severity of the depression, we used the Hamilton depression (Ham-D) rating scale. Serum IL-3 and lipocalin-2 levels were measured using commercially available enzyme-linked immune-sorbent assay kits (ELISA kits). RESULTS: According to this study, we observed elevated serum levels of IL-3 (1,024.73 ± 29.84 pg/mL) and reduced levels of serum lipocalin-2 (29.019 ± 2.073 ng/mL) in MDD patients compared to HCs (911.11 ± 20.55 pg/mL and 48.065 ± 3.583 ng/mL, respectively). No associations between serum levels of IL-3 and lipocalin-2 and depression severity were observed in patients. CONCLUSIONS: According to the present findings, alterations of serum IL-3 and lipocalin might be associated with the pathogenesis of MDD. These results support that altered serum neurochemicals can serve as early risk assessment markers for depression. Further interventional studies are recommended for a better understanding of the role of IL-3 and lipocalin-2 in the pathophysiology of depression.

RUNX1 loss renders hematopoietic and leukemic cells dependent on IL-3 and sensitive to JAK inhibition.

Disease-initiating mutations in the transcription factor RUNX1 occur as germline and somatic events that cause leukemias with particularly poor prognosis. However, the role of RUNX1 in leukemogenesis is not fully understood, and effective therapies for RUNX1-mutant leukemias remain elusive. Here, we used primary patient samples and a RUNX1-KO model in primary human hematopoietic cells to investigate how RUNX1 loss contributes to leukemic progression and to identify targetable vulnerabilities. Surprisingly, we found that RUNX1 loss decreased proliferative capacity and stem cell function. However, RUNX1-deficient cells selectively upregulated the IL-3 receptor. Exposure to IL-3, but not other JAK/STAT cytokines, rescued RUNX1-KO proliferative and competitive defects. Further, we demonstrated that RUNX1 loss repressed JAK/STAT signaling and rendered RUNX1-deficient cells sensitive to JAK inhibitors. Our study identifies a dependency of RUNX1-mutant leukemias on IL-3/JAK/STAT signaling, which may enable targeting of these aggressive blood cancers with existing agents.

IL-3 receptor signalling suppresses chronic intestinal inflammation by controlling mechanobiology and tissue egress of regulatory T cells.

IL-3 has been reported to be involved in various inflammatory disorders, but its role in inflammatory bowel disease (IBD) has not been addressed so far. Here, we determined IL-3 expression in samples from patients with IBD and studied the impact of Il3 or Il3r deficiency on T cell-dependent experimental colitis. We explored the mechanical, cytoskeletal and migratory properties of Il3r -/- and Il3r +/+ T cells using real-time deformability cytometry, atomic force microscopy, scanning electron microscopy, fluorescence recovery after photobleaching and in vitro and in vivo cell trafficking assays. We observed that, in patients with IBD, the levels of IL-3 in the inflamed mucosa were increased. In vivo, experimental chronic colitis on T cell transfer was exacerbated in the absence of Il-3 or Il-3r signalling. This was attributable to Il-3r signalling-induced changes in kinase phosphorylation and actin cytoskeleton structure, resulting in increased mechanical deformability and enhanced egress of Tregs from the inflamed colon mucosa. Similarly, IL-3 controlled mechanobiology in human Tregs and was associated with increased mucosal Treg abundance in patients with IBD. Collectively, our data reveal that IL-3 signaling exerts an important regulatory role at the interface of biophysical and migratory T cell features in intestinal inflammation and suggest that this might be an interesting target for future intervention.