A Three-Generation Muckle-Wells Syndrome Family: Detailed Family History, Physical Examination, and Inter-Departmental Collaboration

Cryopyrin-associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disease caused by gain-of-function mutations in the NLRP3 gene, with a genotype-phenotype correlation. The clinical presentation of each mutation has been previously studied. However, very few studies have reported on the clinical characteristics and treatment effectiveness across different generations within a family with the same mutation. A detailed investigation of family members of patients with CAPS may help in the appropriate diagnosis and treatment of undiagnosed CAPS. Herein, we report a 2-year-old boy (proband), his father, and his grandmother who presented with several symptoms of CAPS, such as persistently positive inflammatory reactions and hearing impairment. All three patients had the same pathogenic mutation in the NLRP3 gene (c.1049C>T (p.Thr350Met) heterozygous mutation) and were diagnosed with CAPS. With canakinumab treatment, the laboratory data of all three patients improved, the proband and father’s skin rash disappeared, and his grandmother’s arthropathy improved. The proband’s hearing also showed slight improvement, but not in his father or grandmother. Among the various non-specific symptoms associated with CAPS, chronic ocular hyperemia is a finding that can be easily identified by non-ophthalmologists. Diagnosis of CAPS should be considered when eye symptoms are present in a combination of hyperinflammatory response, arthropathy, or skin symptoms. Thorough family history records, physical examinations, and close collaboration between pediatricians and adult rheumatologists are important for prompt diagnosis and appropriate treatment of inherited autoinflammatory diseases.

The effect of Borago officinalis on the signaling pathway of the NLRP3 inflammasome complex, TLR4 and some inflammatory cytokines in type II diabetic patients with acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a life-threatening condition in which the lungs become severely inflamed, causing the alveoli to constrict or fill with fluid, which prevents the lungs from functioning properly. This disease becomes more dangerous when it occurs in patients with diabetes. Because of the clinical condition of these patients, it is not possible to treat them with usual medicines. One of the best options for treating these people is to use herbs. Borage (Borago officinalis) is a medicinal herb that, in addition to its anti-inflammatory properties, is also able to control blood sugar. Therefore, in the current study, the effect of borage oil was considered on the signaling pathway of the NLRP3 inflammasome complex, TLR4, and serum levels of inflammatory cytokines (IL-1? and IL-18) in type II diabetic patients with ARDS. For this purpose, 25 diabetic type II patients with ARDS were divided into three groups by ARDS Berlin Definition. Then, after providing the demographic and clinical characteristics of the patients, they were treated with 30 mg/day borage oil for seven days. The expression of NLRP3 and TLR4 genes (by Real-time PCR technique) and serum levels of IL-1? and IL-18 (by ELISA test) were evaluated before and after treatment with borage oil through blood samples taken from patients. The results showed that serum levels of inflammatory cytokines (IL-1? and IL-18), NLRP3 gene, and TLR4 gene were significantly decreased in diabetic type II patients with mild ARDS by treating with borage oil. IL-1? serum level and TLR4 were significantly decreased in diabetic type II patients with moderate ARDS. But there was not any significant decrease or increase in IL-1?, IL-18, NLRP3 gene, and TLR4 gene in diabetic type II patients with severe ARDS after 7 days of treatment with borage oil. According to the obtained results, borage oil can act as a double-edged blade. Thus, in the early and middle stages of ARDS, borage oil can be effective in reducing the inflammasome pathway of inflammation and also reduce blood sugar levels in these diabetic patients. But in the severe stage of ARDS, it not only does not help to treat the ARDS; it also increases systolic and diastolic blood pressure in diabetic patients.

Caspase-3/NLRP3 signaling in the mesenchymal stromal niche regulates myeloid-biased hematopoiesis

Background The fate of hematopoietic stem cells (HSCs) is determined by a complex regulatory network that includes both intrinsic and extrinsic signals. In the past decades, many intrinsic key molecules of HSCs have been shown to control hematopoiesis homeostasis. Non-hematopoietic niche cells also contribute to the self-renewal, quiescence, and differentiation of HSCs. Mesenchymal stromal cells (MSCs) have been identified as important components of the niche. However, the regulatory role of MSCs in hematopoiesis has not been fully understood. Methods Caspase-3 and NLRP3 gene knockout mice were generated respectively, and hematopoietic development was evaluated in the peripheral circulation and bone marrow by flow cytometry, colony formation assay, and bone marrow transplantation. Bone-associated MSCs (BA-MSCs) were then isolated from gene knockout mice, and the effect of Caspase-3/NLRP3 deficient BA-MSCs on hematopoiesis regulation was explored in vivo and ex vivo. Results We report that Caspase-3 deficient mice exhibit increased myelopoiesis and an aberrant HSC pool. Ablation of Caspase-3 in BA-MSCs regulates myeloid lineage expansion by altering the expression of hematopoietic retention cytokines, including SCF and CXCL12. Interestingly, NLRP3 gene knockout mice share phenotypic similarities with Caspase-3 deficient mice. Additionally, we found that NLRP3 may play a role in myeloid development by affecting the cell cycle and apoptosis of hematopoietic progenitors. Conclusions Our data demonstrate that the Caspase-3/NLRP3 signaling functions as an important regulator in physiological hematopoiesis, which provides new insights regarding niche signals that influence hematopoiesis regulation in the bone marrow.

Rare Clinical Case of Cryopyrin-Associated Periodic Syndrome Presented with Ankylosing Spondylitis: A Case Report

Background: Cryopyrin-Associated Periodic Syndrome (CAPS) is a variety of clinical variants of autoinflammatory diseases. The pathology is based on a mutation in the NLRP3 gene encoding the cryopyrin protein, which leads to the uncontrolled production of interleukin-1β. Particular attention should be paid to the rarity of this disease and the lack of clinical knowledge about it in therapeutic and rheumatological practice, which leads to an erroneous diagnosis and the appointment of ineffective treatment for a long time, leading to the progression of the disease and disability of the patient. Case Presentation: This article describes a clinical case of this disease. The first manifestations of the disease in a woman appeared from the age of 2 years, in the form of a rash and fever. Since school age, there have been signs of arthritis. By the age of 24, sensorineural hearing loss and pain in the spine were evident. The disease occurred under the clinical manifestations of spondyloarthritis. Its treatment with anti-inflammatory therapy did not give a stable result. Conclusion: From the analysis, we can conclude that patient M. from early childhood suffers from a severe Neonatal-onset Multisystem Inflammatory Disease of a genetic nature. For a long time, the patient was diagnosed with ankylosing spondylitis, and appropriate treatment was carried out without significant success. The correct diagnosis of CAPS was made only in 2018. This patient has conditions of both CAPS and AS together, which is a very rare association in rheumatological practice. The only treatment method that could stop the manifestations of the disease and prevent life-threatening kidney damage (amyloidosis) is the use of genetically engineered biological drugs, i.e., IL-1β inhibitors. The only drug of this group registered in Russia is canakinumab (Ilaris ®). From the moment of diagnosis to the present day, the patient is treated with the genetically engineered drug canakinumab (Ilaris ®) at a dose of 150 mg once every 8 weeks. 6 months after taking the drug, the patient went into complete clinical and laboratory remission.

Effectiveness of NLRP3 Inhibitor as a Non-Hormonal Treatment for Ovarian Endometriosis

Background Endometriosis is a complex syndrome characterized by an estrogen-dependent chronic inflammatory process that affects 10% of women of reproductive age. Ovarian endometriosis (OE) is the most common lesion in endometriosis and may cause infertility in addition to dysmenorrhea. Hormonal treatments for endometriosis suppress ovulation; hence, they are not compatible with fertility. The inflammasome is a complex that includes Nod-like receptor (NLR) family proteins that sense pathogen-/danger‐associated molecular patterns and homeostasis-altering molecular processes. It has been reported that the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing (NLRP) 3 inflammasome, which contributes to the activation of interleukin-1 beta (IL-1β), might be related to the progression of endometriosis. Therefore, the aim of the present study was to evaluate non-hormonal therapies for OE, such as the inhibitors of the NLRP3 inflammasome. Methods The expression of NLRP3 was measured in the eutopic endometrium (EM) of patients with/without endometriosis and OE and stromal cells derived from the endometrium of patients with endometriosis and OE (endometrial stromal cells [ESCs] and cyst-derived stromal cells [CSCs]). The effect of an NLRP3 inhibitor (MCC950) on ESC and CSC survival and IL-1β production was evaluated. We then administered MCC950 to a murine model of OE to evaluate its effects on OE lesions and ovarian function. Results NLRP3 gene and protein expression levels were higher in OE and CSCs than in EM and ESCs, respectively. MCC950 treatment significantly reduced the survival of CSCs but not that of ESCs. Moreover, MCC950 treatment reduced the co-localization of NLRP3 and IL-1β in CSCs and IL-1β concentrations in CSC supernatants. In the murine model, MCC950 treatment reduced OE lesion size compared to phosphate-buffered saline treatment (89 ± 15 vs. 49 ± 9.3 mm3 per ovary; P < 0.05). In addition, IL-1β and Ki67 levels in the OE-associated epithelia and oxidative stress markers of granulosa cells were reduced in the MCC950-treated group. Conclusions These results indicate that NLRP3/IL-1β is involved in the pathogenesis of endometriosis and that NLRP3 inhibitors may be useful for suppressing OE and improving the function of ovaries with endometriosis.

NLRP3 Inflammasome Blocking as a Potential Treatment of Central Insulin Resistance in Early-Stage Alzheimer’s Disease

Background: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder. In recent years, attention of researchers has increasingly been focused on studying the role of brain insulin resistance (BIR) in the AD pathogenesis. Neuroinflammation makes a significant contribution to the BIR due to the activation of NLRP3 inflammasome. This study was devoted to the understanding of the potential therapeutic roles of the NLRP3 inflammasome in neurodegeneration occurring concomitant with BIR and its contribution to the progression of emotional disorders. Methods: To test the impact of innate immune signaling on the changes induced by Aβ1-42 injection, we analyzed animals carrying a genetic deletion of the Nlrp3 gene. Thus, we studied the role of NLRP3 inflammasomes in health and neurodegeneration in maintaining brain insulin signaling using behavioral, electrophysiological approaches, immunohistochemistry, ELISA and real-time PCR. Results: We revealed that NLRP3 inflammasomes are required for insulin-dependent glucose transport in the brain and memory consolidation. Conclusions NLRP3 knockout protects mice against the development of BIR: Taken together, our data reveal the protective role of Nlrp3 deletion in the regulation of fear memory and the development of Aβ-induced insulin resistance, providing a novel target for the clinical treatment of this disorder.

Immunopathophysiology of Juvenile Spondyloarthritis (jSpA): The “Out of the Box” View on Epigenetics, Neuroendocrine Pathways and Role of the Macrophage Migration Inhibitory Factor (MIF)

Juvenile spondyloarthritis (jSpA) is a an umbrella term for heterogeneous group of related seronegative inflammatory disorders sharing common symptoms. Although it mainly affects children and adolescents, it often remains active during adulthood. Genetic and environmental factors are involved in its occurrence, although the exact underlying immunopathophysiology remains incompletely elucidated. Accumulated evidence suggests that, in affected patients, subclinical gut inflammation caused by intestinal dysbiosis, is pivotal to the future development of synovial–entheseal complex inflammation. While the predominant role of IL17/23 axis, TNF-α, and IL-7 in the pathophysiology of SpA, including jSpA, is firmly established, the role of the cytokine macrophage migration inhibitory factor (MIF) is generally overlooked. The purpose of this review is to discuss and emphasize the role of epigenetics, neuroendocrine pathways and the hypothalamic-pituitary (HPA) axis, and to propose a novel hypothesis of the role of decreased NLRP3 gene expression and possibly MIF in the early phases of jSpA development. The decreased NLRP3 gene expression in the latter, due to hypomethylation of promotor site, is (one of) the cause for inflammasome malfunction leading to gut dysbiosis observed in patients with early jSpA. In addition, we highlight the role of MIF in the complex innate, adaptive cellular and main effector cytokine network, Finally, since treatment of advanced bone pathology in SpA remains an unmet clinical need, I suggest possible new drug targets with the aim to ultimately improve treatment efficacy and long-term outcome of jSpA patients.

Sterile inflammation through Ca2+/ Calmodulin-dependent protein kinase II signaling is essential for adverse cardiac remodeling

Introduction and hypothesis Sterile inflammation is associated with cardiac remodeling in response to non-ischemic stress, but how it is initiated in the absence of cell death and how it is propagated are not well elucidated. We tested the hypothesis that activation of CaMKII in cardiomyocytes and macrophages in response to pressure overload initiates inflammatory responses leading to adverse cardiac remodeling. Methods and results Cardiomyocyte specific CaMKIIδ knockout (CKO) mice were subjected to transverse aortic constriction (TAC). CaMKII and NFkB activation were significantly increased in control fl/fl (CTL) but not in CKO hearts. Cardiac mRNA levels for pro-inflammatory cytokines also increased vs sham. These responses were significantly attenuated in the CKO mice. Activated NLRP3 inflammasome was shown by elevated caspase-1 activity in isolated cardiomyocytes of CTL while attenuated in CKO. Macrophage accumulation was attenuated in the CKO and NLRP3 inhibitor MCC950 treated mice. Cardiac fibrosis and subsequent cardiac dysfunction were less impaired in the CKO vs CTL (ejection fraction 43±3% vs 33±5%). Upregulated NLRP3 gene expression, elevated CaMKII and caspase-1 activity were observed in neonatal mouse cardiomyocytes (NMCMs) in response to osmotic stretch. Increased caspase-1 activity was observed in macrophages cultured with media from osmotic-stretched NMCMs and it was attenuated by pretreatment of CaMKII inhibitor KN-93. Coincubation with stretched NMCMs induced inflammatory responses in isolated macrophages from wild-type mice but not in isolated macrophages from KN-93 pretreated mice. Conclusions Activated CaMKIIδ in response to pressure overload triggers inflammatory signals including NLRP3 inflammasome cascade in cardiomyocytes. CaMKII could also contribute amplification of inflammasome signal in macrophages leading fibrosis and consequent cardiac dysfunction. CaMKII in cardiomyocytes and macrophages could be a therapeutic target to prevent progression of non-ischemic heart failure. FUNDunding Acknowledgement Type of funding sources: None.

Identification of a New Variant in NLRP3 Gene by Whole Exome Sequencing in a Patient with Cryopyrin-Associated Periodic Syndrome

Background. NLRP3 gene is located in chromosome 1 and encodes a pyrin-like protein. Mutations in this gene are associated with an autoinflammatory disease, called cryopyrin-associated periodic syndrome (CAPS). Case Presentation. We report a 1-year-old boy who had recurrent urticarial rash since birth and joint pain and swelling. He had a missense mutation c.G1060 T (p.A354S) in exon 5 of the NLRP3 gene which was detected by whole exome sequencing. Conclusion. A novel variant was found in the NLRP3 gene which has not been reported by now.