Signal Transducer And Activator Of Transcription 3 Deficiency Research Articles

Epidermal keratinocyte-specific STAT3 deficiency aggravated atopic dermatitis-like skin inflammation in mice through TSLP upregulation.

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases with complex pathogenesis involving epidermal barrier dysfunction, skin microbiome abnormalities and type-2-skewed immune dysregulation. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays critical roles in various biological processes. However, the role of STAT3 in epidermal keratinocytes in AD remains unclear. In this study, we generated an epidermal keratinocyte-specific Stat3-deficient mouse strain (termed Stat3 cKO mice). After topical 2,4-dinitrochlorobenzene (DNCB) treatment, Stat3 cKO mice developed worsened AD-like skin inflammation with increased Ki67+ cells, decreased filaggrin and loricrin expression, and downregulated S100A9 and LL37. The dominant microbial population in Stat3 cKO mice changed from Ralstonia to Staphylococcus. DNCB-treated Stat3 cKO mice displayed more infiltrating type-2 inflammatory cells, including mast cells, eosinophils, and CD4+T cells, accompanied by increased skin IL-4 and serum IgE levels. Moreover, thymic stromal lymphopoietin (TSLP), mainly produced by keratinocytes, was highly expressed in the ear skin of Stat3 cKO mice and chemoattracted more TSLPR+ cells. TSLP blockade significantly alleviated DNCB-induced AD-like skin inflammation in Stat3 cKO mice. Thus, epidermal keratinocyte-specific STAT3 deficiency can aggravate AD-like skin inflammation in mice, possibly through TSLP dysregulation.

Inherited human ZNF341 deficiency.

Typical hyper-IgE syndromes (HIES) are caused by autosomal-dominant-negative (DN) variants of STAT3 (Signal Transducer And Activator Of Transcription 3) or IL6ST (Interleukin 6 Cytokine Family Signal Transducer), biallelic partial loss-of-function (LOF) variants of IL6ST, or biallelic complete LOF variants of ZNF341 (Zinc Finger Protein 341). Including the two new cases described in this review, only 20 patients with autosomal-recessive (AR) ZNF341 deficiency have ever been reported. Patients with AR ZNF341 deficiency have clinical and immunological phenotypes resembling those of patients with autosomal-dominant STAT3 deficiency, but with a usually milder clinical presentation and lower NK (Natural Killer) cell counts. ZNF341-deficient cells have 50% the normal level of STAT3 in the resting state. However, as there is no clear evidence that STAT3 haploinsufficiency causes HIES, this decrease alone is probably insufficient to explain the HIES phenotype observed in the ZNF341-deficient patients. The combination of decreased basal expression level and impaired autoinduction of STAT3 observed in ZNF341-deficient lymphocytes is considered a more likely pathophysiological mechanism. We review here what is currently known about the ZNF341 gene and ZNF341 deficiency, and briefly discuss possible roles for this protein in addition to its control of STAT3 activity.

Diagnostic challenge in a series of eleven patients with hyper IgE syndromes.

Hyper IgE syndromes (HIES) is a heterogeneous group of Inborn Errors of Immunity characterized by eczema, recurrent skin and lung infections associated with eosinophilia and elevated IgE levels. Autosomal dominant HIES caused by loss of function mutations in Signal transducer and activator of transcription 3 (STAT3) gene is the prototype of these disorders. Over the past two decades, advent in genetic testing allowed the identification of ten other etiologies of HIES. Although Dedicator of Cytokinesis 8 (DOCK8) deficiency is no more classified among HIES etiologies but as a combined immunodeficiency, this disease, characterized by severe viral infections, food allergies, autoimmunity, and increased risk of malignancies, shares some clinical features with STAT3 deficiency. The present study highlights the diagnostic challenge in eleven patients with the clinical phenotype of HIES in a resource-limited region. Candidate gene strategy supported by clinical features, laboratory findings and functional investigations allowed the identification of two heterozygous STAT3 mutations in five patients, and a bi-allelic DOCK8 mutation in one patient. Whole Exome Sequencing allowed to unmask atypical presentations of DOCK8 deficiency in two patients presenting with clinical features reminiscent of STAT3 deficiency. Our study underlies the importance of the differential diagnosis between STAT3 and DOCK8 deficiencies in order to improve diagnostic criteria and to propose appropriate therapeutic approaches. In addition, our findings emphasize the role of NGS in detecting mutations that induce overlapping phenotypes.

Association of hyper IgE with herpetic viral encephalitis and ecthyma gangrenosum in a male Egyptian patient

There are two forms of hyper-immunoglobulin E syndromes (HIES): a dominant form (AD-HIES) is caused by mutations in signal transducer and activator of transcription 3 (STAT3), and a recessive form (AR-HIES) is caused by mutations in dedicator of cytokinesis 8 (DOCK8). DOCK8 autosomal recessive hyper IgE syndrome (AR-HIES) patients have a more symptomatic neurologic disease than those with STAT3 deficiency. Involvement of the central nervous system in patients with HIES has been rarely reported. Being a rare primary immuno-deficiency, the disease may be underdiagnosed and under-reported. In the central nervous system abnormalities with definite neurologic manifestations, very few articles were published previously which may vary from hemiplegia to partial facial nerve paralysis in children and acute disseminated encephalomyelitis (ADEM), but viral encephalitis has not been reported. Herein, we describe a 21-year-old male with hyper-immunoglobulin E syndrome presented with fever, pneumonia, skin abscesses, and altered consciousness who proved to have herpetic viral encephalitis. The purpose of this study is to emphasize that neurologic complications with herpetic viral encephalitis may occur in patients with hyper IgE syndrome. In the case series, no cases of hyper IgE were described to have viral encephalitis, and to the best of our knowledge, this is the first description of herpes simplex encephalitis in a patient with hyper IgE syndrome.

A CASE OF PULMONARY EMBOLISM POST COVID-19 INFECTION IN A PATIENT WITH STAT3 MUTATION

<h3>Introduction</h3> Signal transducer and activator of transcription 3 (STAT3) is a transcriptional regulator that plays an important role in controlling the innate and adaptive immune system. Hyper IgE syndrome, caused by a STAT3 deficiency, is a rare disorder that commonly presents with connective tissue, skeletal, and vascular abnormalities. Known vasculopathies seen in this syndrome include aneurysms and thrombotic events frequently in coronary and cerebral vascular systems. <h3>Case Description</h3> We report a 55-year-old white male with a known STAT3 deficiency based on clinical symptomology and genetic testing. The patient has been on monthly intravenous immunoglobulin therapy. He has refused active and passive immunization to COVID-19 due to religious reasons. Soon after a COVID-19 infection he presented with dyspnea, leg swelling, and chest pain. Worsening symptoms caused him to be admitted to the hospital and a V/Q scan was performed. The result showed a pulmonary embolism of the left lower lobe, he was treated for this condition and then discharged from the hospital. <h3>Discussion</h3> STAT3 deficient patients typically present with a triad of symptoms: eosinophilia, atopic dermatitis, and pulmonary/skin infections. The complication of recurrent vasculopathies, including clots, has been seen in many patients with a STAT3 deficiency. Outside of STAT3 deficient patients, there has been multiple clinical scenarios where pulmonary embolisms have been present in patients after a COVID-19 infection. This is the first published case of a STAT3 deficient patient presenting with a pulmonary embolism due to a COVID infection.

A mitochondrial STAT3-methionine metabolism axis promotes ILC2-driven allergic lung inflammation

Group 2 innate lymphoid cells (ILC2s), the innate counterpart of TH2 cells, play a critical role in type 2 immune responses. However, the molecular regulatory mechanisms of ILC2s are still unclear. The aim of this study was to explore the importance of signal transducer and activator of transcription 3 (STAT3) to ILC2 function in allergic lung inflammation. Acute and chronic asthma models were established by intranasal administration of the protease allergen papain in VavicreStat3fl/fl, Il5tdtomato-creStat3fl/fl, and RorccreStat3fl/fl mice to verify the necessity of functional STAT3 for ILC2 allergic response. The intrinsic role of STAT3 in regulating ILC2 function was examined by generation of bone marrow chimera mice. The underlying mechanism was studied through confocal imaging, metabolomics analysis, and chromatin immunoprecipitation quantitative PCR. STAT3 is essential for ILC2 effector function and promotes ILC2-driven allergic inflammation in the lung. Mechanistically, the alarmin cytokine IL-33 induces a noncanonical STAT3 phosphorylation at serine 727 in ILC2s, leading to translocation of STAT3 into the mitochondria. Mitochondrial STAT3 further facilitates adenosine triphosphate synthesis to fuel the methionine cycle and generation of S-adenosylmethionine, which supports the epigenetic reprogramming of type 2 cytokines in ILC2s. STAT3 deficiency, inhibition of STAT3 mitochondrial translocation, or blockade of methionine metabolism markedly dampened the ILC2 allergic response and ameliorated allergic lung inflammation. The mitochondrial STAT3-methionine metabolism pathway is a key regulator that shapes ILC2 effector function through epigenetic regulation, and the related proteins or metabolites represent potential therapeutic targets for allergic lung inflammation.

Emergence of azole resistant-Aspergillus fumigatus infections during STAT3-deficiency

Introduction. Signal transducer and activator of transcription 3 (STAT3) deficiency is a rare primary immunodeficiency associated with increased susceptibility to bacterial and fungal infections, notably pulmonary aspergillosis.Aim. We describe the emergence of azole-resistant Aspergillus fumigatus infections in STAT3-deficient patients.Methodology. During a retrospective study of 13 pulmonary aspergillosis cases in STAT3-deficient patients conducted in France, we identified patients infected with azole-resistant A. fumigatus isolates.Results. Two out of the 13 STAT3-deficient patients with aspergillosis had azole-resistant A. fumigatus infection, indicating an unexpectedly high prevalence of resistance. The first patient with STAT3 deficiency presented several flares of allergic bronchopulmonary aspergillosis-like episodes. He was chronically infected with two azole-resistant A. fumigatus isolates (TR34/L98). Despite prolonged antifungal treatment, including caspofungin and amphotericin B, the patient was not able to clear the azole-resistant A. fumigatus. The second patient had chronic cavitary pulmonary aspergillosis (CCPA). The A. fumigatus isolate was initially azole susceptible but harboured three F46Y, M172V and E427K point mutations. Despite prolonged antifungal therapies, lesions worsened and the isolate became resistant to all azoles. Surgery and caspofungin treatments were then required to cure CCPA. Resistance was probably acquired from the environment (TR34/L98) in the first case whereas resistance developed under antifungal treatments in the second case. These infections required long-term antifungal treatments and surgery.Conclusions. The emergence of azole-resistant A. fumigatus infections in STAT3-deficiency dramatically impacts both curative and prophylactic antifungal strategies. Physicians following patients with primary immune-deficiencies should be aware of this emerging problem as it complicates management of the patient.

Transcription factor signal transducer and activator of transcription 3 (STAT-3) serves as a negative regulator controlling IgE class switching

Abstract A mutation in the Signal Transducer and Activator of Transcription 3 (STAT-3) has been linked to incidence of Autosomal Dominant Hyper Immunoglobulin E Syndrome (AD-HIES), a disease characterized by elevated serum IgE antibody and susceptibility to respiratory and skin infection. However, how this genetic mutation leads to the phenotype has not been fully understood. In this study we investigated the specific role of STAT-3 in the germinal center (GC) B cells and plasma cells for IgE class switching. Through the use of CD2-Cre or CD19-Cre driven STAT-3 conditional knockout (cKO) mice in a Th2-type immunization model, we aimed to determine the specific cell subset(s) and signaling mechanism by which STAT-3 mediated class switching is regulated. We demonstrated in vivo and in vitro that CD2-Cre driven STAT-3 cKO mice showed elevated IgE and decreased IgG1 in the serum, and a reduction in GC formation. Within the GC, IgG1+ GC B cells were decreased while IgE+ GC B cells were more prevalent. Additionally, these mice exhibited reduced IgG1 and elevated IgE populations of antibody-producing plasma cells. Subsequent experiments using a CD19-Cre B-cell specific cKO mouse established this effect to be B-cell intrinsic. Mice with STAT-3 deficiency in B cells have also demonstrated an increase in lung inflammation when used in an asthma-like disease model. Our data also revealed other transcription factors, including Bcl-6 and Aicda, function as downstream signals of STAT-3 regulation. This model suggests a negative role for STAT-3 in regulating class switching of the GC B cells from the IgG1 to the IgE producing state, which may serve as a therapeutic target for treatment of AD-HIES and other immune disorders.

T Cell-Specific Knockout of STAT3 Ameliorates Dextran Sulfate Sodium-Induced Colitis by Reducing the Inflammatory Response.

Signal transducer and activator of transcription 3 (STAT3) has a crucial role in various autoimmune disorders including, inflammatory bowel disease (IBD). Our previous study demonstrated that STAT3 activation by IL-6 in colonic epithelial cells exacerbates experimental ulcerative colitis. Activated T lymphocytes are also found in ulcerative colitis patients with intestinal inflammation, but the role of STAT3 in T cells remains elusive. To determine the STAT3 function of T cells in intestinal inflammation, we generated T cell-specific STAT3 knockout (KO) mice and used dextran sulfate sodium (DSS) to induce colitis. In this study, we demonstrated that T cell-specific STAT3 deletion alleviated DSS-induced colitis in mice, resulting in reduced histological scores and myeloperoxidase (MPO) activity. Importantly, the population of T cells in the spleen and lymph nodes was significantly decreased in the control and DSS-induced groups of STAT3 KO mice. In addition, STAT3 deficiency in T cells markedly reduced the production of interferon (IFN)-γ, IL-6, and IL-17A, whereas IL-10 secretion was increased. Collectively, the results suggest that STAT3 in T cells may be a therapeutic target in ulcerative colitis by balancing the immune response through T cell homeostasis.

Abstract 618: Hypoxia Inducible Factor 1a Stabilization in Autosomal Dominant Hyper IgE Syndrome Fibroblasts Rescues Impaired Ability to Support Angiogenesis

Background: Autosomal dominant Hyper-IgE syndrome (AD-HIES) is a rare primary immunodeficiency caused by dominant negative mutations in signal transducer and activator of transcription 3 (STAT3 ) , a mediator of widespread physiological processes. It is characterized by dermatitis, recurrent infections, elevated IgE, poor post-surgical healing, and connective tissue abnormalities. How STAT3 deficiency leads to this phenotype, however, is not known. Current treatment options are limited to antimicrobials for infection control. The aim of this study was to investigate which of STAT3’s many functions are dis-regulated in AD-HIES, and where potential targets for therapy may lie. Methods: We used skin fibroblasts (SF) from 3 AD-HIES patients and 3 normal volunteers. To evaluate potentially affected pathways, we utilized RNA- Seq and subsequent Gene Set Enrichment (GSEA) and pathway analysis (Pathway Studio, GeneGo Metacore). Endothelial cell tube formation assay was used to assess ability of AD-HIES SFs to support angiogenesis. Results: GSEA and pathway analysis showed deficiencies in signaling pathways linked to wound healing, extracellular matrix remodeling and angiogenesis including targets of Hypoxia Inducible Factor 1a (HIF1a) (P values for enrichments &lt; 0.001) . Therefore, we hypothesized that AD-HIES SFs have impaired ability to support angiogenesis due to deficient Hif1a-dependent secretion of matrix proteases and growth factors. Indeed, AD-HIES SF secreted up to 5 times less matrix metalloprotease 1, 3, and 9, placental growth factor and fibroblast growth factors 1 and 2 (Luminex Multiplex, n=3-9, P&lt;0.05). Culture medium from AD-HIES SFs failed to fully support tube formation by endothelial cells resulting in lower number of junctions, meshes, and total tubule length (n=6, P&lt;0.005). Stabilization of Hif1a in AD-HIES SFs by prolyl hydroxylase inhibitor dimethyl fumarate restored its transcriptional activity leading to increased number of junctions, meshes, and tubule length (n=12, P&lt;0.05) Conclusion: AD-HIES SFs have deficiencies in pro-angiogenic signaling pathways that lead to decreased growth factor secretion and angiogenesis. Stabilization of HIF1a corrects this deficiency and is an enticing target for future therapy.

Cardiac STAT3 Deficiency Impairs Contractility and Metabolic Homeostasis in Hypertension.

Signal transducer and activator of transcription 3 (STAT3) protects the heart from acute ischemic stress. However, the importance of STAT3 to the heart in chronic stress, such as hypertension, is not known. To study this, we used cardiomyocyte-targeted STAT3 knockout (KO) mice and Angiotensin II (ANG II) infusion by osmotic minipumps. After 4 weeks, ANG II induced similar cardiac hypertrophy in wild type (WT) and cardiac Cre-expressing control (CTRL) mice with no impairment of cardiac function. In contrast, STAT3 KO mice exhibited reduced contractile function but similar hypertrophy to CTRL mice. Ejection fraction and fractional shortening decreased by 22.5 and 27.3%, respectively. Since STAT3 has direct protective effects on mitochondrial function, we examined rates of glucose and oleate oxidation by isolated perfused hearts using a Langendorff system. Hearts of ANG II-treated STAT3 KO and CTRL mice had similar rates of oleate oxidation as saline-infused WT mice. Rates of glucose oxidation were similar between hearts of WT plus saline and CTRL plus ANG II mice; however, glucose oxidation was increased by 66% in hearts of ANG II-treated STAT3 KO mice. The ratio of maximal ATP yield from glucose to fatty acid oxidation was 21.1 ± 3.1 in hearts of ANG II-treated STAT3 KO mice vs. 12.6 ± 2.2 in hearts of ANG II-treated CTRL mice. Lactate production was also elevated in hearts of ANG II-treated STAT3 KO mice by 162% compared to ANG II-treated CTRL mice. Our findings indicate that STAT3 is important for maintaining contractile function and metabolic homeostasis in the hypertensive heart, and STAT3 deficiency promotes a switch toward glucose utilization.

The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency

Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management. We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings. Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations. DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/μL (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4(+) and CD8(+) T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). Acombination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations. DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures.

Altered Islet Morphology but Normal Islet Secretory Function In Vitro in a Mouse Model with Microvascular Alterations in the Pancreas

BackgroundOur previous studies have shown that signal transducer and activator of transcription 3 (STAT3) signaling is important for the development of pancreatic microvasculature via its regulation of vascular endothelial growth factor-A (VEGF-A). Pancreas-specific STAT3-KO mice exhibit glucose intolerance and impaired insulin secretion in vivo, along with microvascular alterations in the pancreas. However, the specific role of STAT3 signaling in the regulation of pancreatic islet development and function is not entirely understood.Methodology/Principal FindingsTo investigate the role of STAT3 signaling in the formation and maintenance of pancreatic islets, we studied pancreas-specific STAT3-KO mice. Histological analysis showed that STAT3 deficiency affected pancreatic islet morphology. We found an increased proportion of small-sized islets and a reduced fraction of medium-sized islets, indicating abnormal islet development in STAT3-KO mice. Interestingly, the islet area relative to the whole pancreas area in transgenic and control mice was not significantly different. Immunohistochemical analysis on pancreatic cryosections revealed abnormalities in islet architecture in STAT3-KO mice: the pattern of peripheral distribution of glucagon-positive α-cells was altered. At the same time, islets belonging to different size categories isolated from STAT3-KO mice exhibited normal glucose-stimulated insulin secretion in perifusion experiments in vitro when compared to control mice.ConclusionsOur data demonstrate that STAT3 signaling in the pancreas is required for normal islet formation and/or maintenance. Altered islet size distribution in the KO mice does not result in an impaired islet secretory function in vitro. Therefore, our current study supports that the glucose intolerance and in vivo insulin secretion defect in pancreas-specific STAT3-KO mice is due to altered microvasculature in the pancreas, and not intrinsic beta-cell function.

Signal Transducer and Activator of Transcription 3 (STAT3) Regulates Collagen-Induced Platelet Aggregation Independently of Its Transcription Factor Activity

Platelet hyperactivity induced by inflammation is a known risk factor for atherosclerosis and thrombosis, but its underlying mechanisms remain poorly understood. The signal transducer and activator of transcription 3 (STAT3) was activated in collagen-stimulated platelets. Activated STAT3 served as a protein scaffold to facilitate the catalytic interaction between the kinase Syk (spleen tyrosine kinase) and the substrate PLCγ2 to enhance collagen-induced calcium mobilization and platelet activation. The same interaction of STAT3 with Syk and PLCγ2 was detected in HEK293 cells transfected with cDNAs for Syk and PLCγ2 and stimulated with interleukin-6. Pharmacological inhibition of STAT3 blocked ≈50% of collagen- and a collagen-related peptide-induced but not thrombin receptor-activating peptide- or ADP-induced aggregation and ≈80% of thrombus formation of human platelets on a collagen matrix. This in vitro phenotype was reproduced in mice infused with STAT3 inhibitors and mice with platelet-specific STAT3 deficiency. By forming a complex with its soluble receptor, the proinflammatory cytokine interleukin-6 enhanced the collagen-induced STAT3 activation in human platelets. These data demonstrate a nontranscriptional activity of STAT3 that facilitates a crosstalk between proinflammatory cytokine and hemostasis/thrombosis signals in platelets. This crosstalk may be responsible for the platelet hyperactivity found in conditions of inflammation.

Reduction of STAT3 expression induces mitochondrial dysfunction and autophagy in cardiac HL-1 cells

Signal transducer and activator of transcription 3 (STAT3) is an important mediator of cardiac survival pathways. Reduced levels of STAT3 in patients with end-stage heart failure suggest a clinical relevance of STAT3 deficiency for cardiac disease. The recent identification of STAT3 as a mitochondrial protein which is important for full activity of mitochondrial complex I has opened a new field for the investigation of how STAT3 functions in cardioprotection. The goal of this study was to establish a cell culture model with a reduced STAT3 expression, and to use this model for the investigation of mitochondrial and mitochondrial-associated functions under STAT3 deficiency. In the murine cardiomyogenic cell line HL-1, the expression of STAT3 was silenced by lentiviral transduction with anti-STAT3 shRNA (STAT3 KD cells). STAT3 mRNA and protein levels were significantly reduced in HL-1 STAT3 KD cells compared to HL-1 cells transduced with a control shRNA. Spectrophotometric and polarographic assays with mitochondrial enriched fractions and intact cells showed reduced activities of respiratory chain complexes I, II, III and IV in HL-1 STAT3 KD cells. At ultrastructural level, a severe damage of mitochondrial integrity was observed, combined with a significant increase in autophagolysosomes in STAT3-deficient HL-1 cells. Our results demonstrate that the HL-1 STAT3 KD cell line is a good model to study cellular consequences of STAT3 deficiency. Moreover, this is the first study to show that STAT3 deficiency leads to a disruption of mitochondrial ultrastructure and increased autophagy.

Autosomal Dominant STAT3 Deficiency and Hyper-IgE Syndrome

Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.

Frequent and Widespread Vascular Abnormalities in Human Signal Transducer and Activator of Transcription 3 Deficiency

Signal transducer and activator of transcription 3 (STAT3) deficiency is responsible for autosomal dominant hyperimmunoglobulin E syndrome, characterized by recurrent bacterial and fungal infections, connective tissue abnormalities, hyperimmunoglobulin E, and Th17 lymphopenia. Although vascular abnormalities have been reported in some patients, the prevalence, characteristics, and etiology of these features have yet to be described. We prospectively screened 21 adult STAT3-deficient patients [corrected] (median age, 26 years; range, 17-44 years) [corrected] for vascular abnormalities. We explored the entire arterial vasculature with whole-body magnetic resonance imaging angiography, coronary multislice computed tomography, and echo-tracking-based imaging specifically for the [corrected] carotid arteries. We also assayed for serum biomarkers of inflammation and endothelial dysfunction. Finally, we studied murine models of aortic aneurysm in the presence and absence of inhibitors of STAT3-dependent signaling. Ninety-five percent of patients showed brain abnormalities (white matter hyperintensities, lacunar lesions suggestive of ischemic infarcts, and atrophy). We reported peripheral and brain artery abnormalities in 84% of the patients and detected coronary artery abnormalities in 50% of the patients. The most frequent vascular abnormalities were ectasia and aneurysm. The carotid intima-media thickness was markedly decreased, with a substantial increase in circumferential wall stress, indicating the occurrence of hypotrophic arterial remodeling in this STAT3-deficient population. Systemic inflammatory biomarker levels correlated poorly with the vascular phenotype. In vivo inhibition of STAT3 signaling or blockade of IL-17A resulted in a marked increase in aneurysm severity and fatal rupture in mouse models. Vascular abnormalities are highly prevalent in patients with STAT3 deficiency. This feature is consistent with the greater susceptibility to vascular aneurysm observed after inhibition of STAT3-dependent signaling in mouse models.

IL-1 and TNF -initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes irreversible joint damage and significant disability. However, the fundamental mechanisms underlying how inflammation and joint destruction in RA develop and are sustained chronically remain largely unknown. Here, we show that signal transducer and activator of transcription 3 (STAT3) is the key mediator of both chronic inflammation and joint destruction in RA. We found that inflammatory cytokines highly expressed in RA patients, such as IL-1β, tumor necrosis factor alpha and IL-6, activated STAT3 either directly or indirectly and in turn induced expression of IL-6 family cytokines, further activating STAT3 in murine osteoblastic and fibroblastic cells. STAT3 activation also induced expression of receptor activator of nuclear factor kappa B ligand (RANKL), a cytokine essential for osteoclastogenesis, and STAT3 deficiency or pharmacological inhibition promoted significant reduction in expression of both IL-6 family cytokines and RANKL in vitro. STAT3 inhibition was also effective in treating an RA model, collagen-induced arthritis, in vivo through significant reduction in expression of IL-6 family cytokines and RANKL, inhibiting both inflammation and joint destruction. Leukemia inhibitory factor expression and STAT3 activation by IL-1β were mainly promoted by IL-6 but still induced in IL-6-deficient cells. Thus, our data provide new insight into RA pathogenesis and provide evidence that inflammatory cytokines trigger a cytokine amplification loop via IL-6-STAT3 that promotes sustained inflammation and joint destruction.

STAT3 controls myeloid progenitor growth during emergency granulopoiesis

AbstractGranulocyte colony-stimulating factor (G-CSF) mediates “emergency” granulopoiesis during infection, a process that is mimicked by clinical G-CSF use, yet we understand little about the intracellular signaling cascades that control demand-driven neutrophil production. Using a murine model with conditional deletion of signal transducer and activator of transcription 3 (STAT3) in bone marrow, we investigated the cellular and molecular mechanisms of STAT3 function in the emergency granulopoiesis response to G-CSF administration or infection with Listeria monocytogenes, a pathogen that is restrained by G-CSF signaling in vivo. Our results show that STAT3 deficiency renders hematopoietic progenitor cells and myeloid precursors refractory to the growth-promoting functions of G-CSF or L monocytogenes infection. STAT3 is necessary for accelerating granulocyte cell-cycle progression and maturation in response to G-CSF. STAT3 directly controls G-CSF–dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. These results place STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF–responsive myeloid progenitor expansion.

Clinical Manifestations, Etiology, and Pathogenesis of the Hyper-IgE Syndromes

Autosomal dominant Hyper-IgE syndrome (AD-HIES) is a rare primary immunodeficiency characterized by eczema, recurrent skin and lung infections, elevated serum IgE, and various connective tissue, skeletal, and vascular abnormalities. Mutations in signal transducer and activator of transcription 3 (STAT3) have recently been found to account for most cases; however, the pathogenesis of the varied features remains poorly defined. A distinct syndrome, known as autosomal recessive HIES (AR-HIES) manifests as severe eczema, recurrent bacterial and viral skin infections, and sinopulmonary infections. As opposed to STAT3 deficient HIES, AR-HIES lacks the connective tissue and skeletal manifestations but has an increase in neurologic abnormalities. In this review, we discuss the clinical presentations, genetic etiologies, and immunologic abnormalities of these two syndromes. In addition, we discuss animal models of STAT3 deficiency that provide insight into the pathogenesis of HIES. Further understanding of how STAT3 results in the diverse manifestations of HIES will allow us to develop more specific therapies for HIES as well as for many of the manifestations, such as scoliosis, recurrent staphylococcal infections, and eczema, which are common in the general population.