Comparative Effects of Intra-Articular versus Intravenous Mesenchymal Stromal Cells Therapy in a Rat Model of Osteoarthritis by Destabilization of Medial Meniscus.

Transplanted mesenchymal stromal cells (MSCs) exhibit a robust anti-inflammatory and homing capacity in response to high inflammatory signals, as observed in studies focused on rheumatic diseases that target articular cartilage (AC) health. However, AC degradation in osteoarthritis (OA) does not necessarily coincide with a highly inflammatory joint profile. Often, by the time patients seek medical attention, they already have damaged AC. In this study, we examined the therapeutic potential of a single bone marrow MSC transplant (2 × 106 cells/kgbw) through two different routes: intra-articular (MSCs-IAt) and intravenous (MSCs-IVt) in a preclinical model of low-grade inflammatory OA with an established AC degeneration. OA was induced through the destabilization of the medial meniscus (DMM) in female Wistar Kyoto rats. The animals received MSCs 9 weeks after surgery and were euthanized 4 and 12 weeks post-transplant. In vivo and ex vivo tracking of MSCs were analyzed via bioluminescence and imaging flow cytometry, respectively. Cytokine/chemokine modulation in serum and synovial fluid was measured using a multiplex panel. AC degeneration was quantified through histology, and hindlimb muscle balance was assessed with precision weighing. To our knowledge, we are the first group to show the in vivo (8 h) and ex vivo (12 h) homing of cells to the DMM-OA joint following MSCs-IVt. In the case of MSCs-IAt, the detection of cellular bioluminescence at the knee joint persisted for up to 1 week. Intriguingly, intra-articular saline injection (placebo-IAt) resulted in a worse prognosis of OA when compared to a non-invasive control (placebo-IVt) without joint injection. The systemic cytokines/chemokines profile exhibited a time-dependent variation between transplant routes, displaying a transient anti-inflammatory systemic response for both MSCs-IVt and MSCs-IAt. A single injection of MSCs, whether administered via the intra-articular or intravenous route, performed 9 weeks after DMM surgery, did not effectively inhibit AC degeneration when compared to a non-invasive control.

Unknown/enigmatic functions of extracellular ASC.

Apoptosis-associated speck-like protein containing a caspase recruit domain (ASC), encoded by PYCARD gene, is a 22 kDa small molecule, which aggregates into ASC specks during inflammasome activation. ASC protein is an adaptor protein present in several inflammasome complexes that performs several intra- and extracellular functions, in monomeric form or as ASC specks, during physiological and pathological processes related to inflammation and adaptive immunity. Extracellular ASC specks (eASC specks) released during cell death by pyroptosis can contribute as a danger signal to the propagation of inflammation via phagocytosis and activation of surrounding cells. ASC specks are found in the circulation of patients with chronic inflammatory diseases and have been considered as relevant blood biomarkers of inflammation. eASC amplifies the inflammatory signal, may induce the production of autoantibodies, transports molecules that bind to this complex, contributing to the generation of antibodies, and can induce the maturation of cytokines promoting the modelling of the adaptive immunity. Although several advances have been registered in the last 21 years, there are numerous unknown or enigmatic gaps in the understanding of the role of eASC specks in the organism. Here, we provide an overview about the ASC protein focusing on the probable roles of eASC specks in several diseases, up to the most recent studies concerning COVID-19.

Hydrothermally-altered feldspar as an environmentally-friendly technology to promote heavy metals immobilization: Batch studies and application in smelting-affected soils.

Hydrothermally-altered feldspar (HydroPotash, HYP) possesses, among other physicochemical properties, high pH buffering and cation exchange capacity. Therefore, it may potentially remove heavy metals from aqueous solutions and immobilize these metals in contaminated soil. This study aimed to evaluate the capabilities of two types of HydroPotash (HYP-1 and HYP-2) and a zeolite sample (a commercial adsorbent) for immobilizing cadmium (Cd), zinc (Zn), and lead (Pb) from both aqueous solution and contaminated soils from a Zn-smelting area (classified as soilhigh, soilintermediate, and soillow based on their level of soluble metal concentration). Sorption studies in natural suspension pH showed that HYPs removed 63.8-99.9% Zn, 20.6-40.7% Cd, and 68.4-99.7% Pb from aqueous solution. In the batch test with controlled pH (at pH 5.5), HYPs sorbed more Cd than zeolite. Analyses of scanning electron microscopy-energy dispersive X-ray spectroscopy after desorption showed the presence of Pb at HYP-2, indicating that this metal was effectively adsorbed. In soilhigh HYPs immobilized 99.9% of Zn, Cd, and Pb after one week of soil incubation with these products. The HYPs immobilization effect persisted up to 84 days of soil incubation with these products. The increased soil pH promoted by HYPs appears to be the main factor controlling metal sorption. In conclusion, HydroPotash can be used as an adsorbent/amendment to effectively immobilize heavy metals in both water and contaminated soils by precipitation and adsorption. Our findings indicate the high potential of this material for Cd, Zn, and Pb stabilization, which is of great relevance when recovering areas affected by mining/smelting activities with multi-element contamination.

Feasibility, safety and efficacy of exercise training in immune-mediated necrotising myopathies: a quasi-experimental prospective study.

OBJECTIVES: To evaluate the feasibility, safety and efficacy of exercise training in patients with immune-mediated necrotising myopathies (IMNM). METHODS: Eight consecutive sedentary patients with IMNM (5 anti-signal recognition particle and 3 anti-hydroxy-methyl-glutaryl coenzyme A reductase) were engaged in this study. Disease status was based on International Myositis Assessment and Clinical Studies Group (IMACS) core set measures. Physical performance was evaluated by cardiopulmonary exercise test, repetition maximum (RM) protocol, handgrip dynamometry, sit-to-stand (STS) and timed up-and-go (TUG) tests. All these parameters were measured at baseline and after a 12-week, twice-a-week, supervised exercise training comprising aerobic and strength exercises. RESULTS: Patients (aged 61 years on average) were very disabled at the beginning of the disease (mean duration of 17.7 months), but after being aggressively treated with a treat-to-target approach, they presented only mild symptoms that were well-controlled with oral immunosuppression and low disease status scores by the time of the exercise intervention. No disease relapsing, worsening of the IMACS set scores or adverse events were observed throughout the training period. Patients also increased aerobic capacity (e.g. time to achieve anaerobic threshold and time to achieve exhaustion), muscle strength (e.g. 1RM bench press) and function (e.g. STS test). CONCLUSIONS: Supervised exercise training did not impair disease status and seemed to be feasible, safe and effective in patients with IMNM. Moreover, exercise training increased aerobic capacity, muscle strength and function, suggesting that this could be a novel potential coadjuvant therapy in IMNM.

Intravenous human immunoglobulin and/or methylprednisolone pulse therapies as a possible treat-to-target strategy in immune-mediated necrotizing myopathies.

To evaluate the relevance of immunoglobulin (IVIg) and/or methylprednisolone pulse therapies in immune-mediated necrotizing myopathy (IMNM). Secondarily, to analyze the muscle damage measured by late magnetic resonance images (MRI). This retrospective study included 13 patients with defined IMNM (nine patients positive for the anti-signal recognition particle and four patients positive for hydroxyl-methyl-glutaryl coenzyme A reductase) who were followed from 2012 to 2018. International Myositis Assessment and Clinical Studies Group (IMACS) scoring assessed the response to a standardized treat-to-target protocol with disease activity core-set measures and late magnetic resonance imaging (MRI). The patients had a mean age of 53.5 years and were predominantly female and of white ethnicity. Median symptom and mean follow-up durations were 4 and 39 months, respectively. All patients received IVIg and/or methylprednisolone pulse therapies. All IMACS core-set measurements improved significantly after initial treatment. Nine patients achieved complete clinical response and among them 2 had complete remission. Eleven patients had discontinued glucocorticoid use by the end of the study. Only 2 patients had moderate muscle atrophy or fat replacement observed by MRI, with the remainder presenting normal or mild findings. Our patients with IMNM treated with an aggressive immunosuppressant therapy had a marked improvement in all IMACS core-set domains. Moreover, the MRI findings suggest that an early treat-to-target approach could reduce the odds of long-term muscle disability. Methylprednisolone and/or IVIg pulse therapies aiming at a target of complete clinical response are potential treatment strategies for IMNM that should be studied in future prospective studies.

Central Nervous System Involvement in Systemic Autoimmune Rheumatic Diseases-Diagnosis and Treatment.

Central nervous system (CNS) involvement in autoimmune rheumatic diseases represents a significant challenge for clinicians across all specialties. While most reviews on the subject focus on neurological manifestations within a specific rheumatic disease, few descriptions shift from neurological clinical syndromes to achieve rheumatological diagnoses. This narrative review aims to synthesize current knowledge on the diagnosis and management of CNS manifestations occurring in the most prevalent rheumatic conditions in adults. We searched the MEDLINE database using the terms "central nervous system", "rheumatic diseases", "systemic lupus erythematosus", "rheumatoid arthritis", "Sjögren syndrome", and "vasculitis". The search strategy included review articles from 2019 to 2024, published in English, Spanish, or Portuguese. We explored the pathophysiological mechanisms linking autoimmunity to CNS pathology, emphasizing the role of syndromic reasoning, autoantibody profiles, and imaging modalities as tools for diagnosis and determination of inflammatory activity. The review also discusses differential diagnoses through a stepwise approach to neurological syndromes, summarized in diagnostic flowcharts, and presents updated treatment options. Although our approach is primarily semiology-based, the complexity of the subject invites future endeavors involving new technologies, such as functional MRI, MR spectroscopy, and nuclear medicine.

Clinically amyopathic dermatomyositis associated with cutaneous ulcerations: a case-based review.

Introduction and importance: Dermatomyositis (DM) is an autoimmune myopathy primarily affecting both muscles and skin. When muscle weakness is not clinically apparent, but characteristic skin lesions are present, the condition is referred to as clinically amyopathic dermatomyositis (CADM). Case presentation: The authors present the case of a 52-year-old female with a typical DM rash, interstitial pneumonia, and multiple skin ulcers. The skin biopsy was consistent with DM, and there were no signs of muscle involvement. Myositis-related and myositis-specific autoantibodies were also negative. Significant improvement was not observed until the patient received successive monthly pulses of methylprednisolone and the introduction of methotrexate. This treatment regimen allowed for the complete tapering of prednisone and resulted in sustained disease control. Clinical discussion: In addition to the case presentation, a narrative literature review was conducted using the MEDLINE database, and an evidence-based treatment flowchart is proposed. CADM is a subtype of DM, related to higher incidences of interstitial lung disease, skin vasculopathy and malignancy. When ulcers or interstitial pneumonia are present, treatment should be early and aggressive. Active screening for neoplasms is recommended, particularly within the first 5 years. Conclusion: The authors presented a case of seronegative CADM featuring skin vasculopathy, successfully treated with consecutive methylprednisolone pulses. Our literature review emphasized the importance of focused CADM management trials, highlighting the need for further research.

Snake and arthropod venoms: Search for inflammatory activity in human cells involved in joint diseases.

Most anti-inflammatory drugs currently adopted to treat chronic inflammatory joint diseases can alleviate symptoms but they do not lead to remission. Therefore, new and more efficient drugs are needed to block the course of joint inflammatory diseases. Animal venoms, rich in bioactive compounds, can contribute as valuable tools in this field of research. In this study, we first demonstrate the direct action of venoms on cells that constitute the articular joints. We established a platform consisting of cell-based assays to evaluate the release of cytokines (IL-6, IL-8, TNFα, IL-1ß, and IL-10) by human chondrocytes, synoviocytes and THP1 macrophages, as well as the release of neuropeptides (substance-P and ß-endorphin) by differentiated sensory neuron-like cells, 24 h after stimulation of cells with 21 animal venoms from snake and arthropod species, sourced from different taxonomic families and geographic origins. Results demonstrated that at non-cytotoxic concentrations, the venoms activate at varying degrees the secretion of inflammatory mediators involved in the pathology of articular diseases, such as IL-6, IL-8, and TNF-α by chondrocytes, synoviocytes, and macrophages and of substance P by neuron-like cells. Venoms of the Viperidae snake family were more inflammatory than those of the Elapidae family, while venoms of Arthropods were less inflammatory than snake venoms. Notably, some venoms also induced the release of the anti-inflammatory IL-10 by macrophages. However, the scorpion Buthus occitanus venom induced the release of IL-10 without increasing the release of inflammatory cytokines by macrophages. Since the cell types used in the experiments are crucial elements in joint inflammatory processes, the results of this work may guide future research on the activation of receptors and inflammatory signaling pathways by selected venoms in these particular cells, aiming at discovering new targets for therapeutic intervention.

A novel proteasome inhibitor acting in mitochondrial dysfunction, ER stress and ROS production.

In cancer-treatment, potentially therapeutic drugs trigger their effects through apoptotic mechanisms. Generally, cell response is manifested by Bcl-2 family protein regulation, the impairment of mitochondrial functions, and ROS production. Notwithstanding, several drugs operate through proteasome inhibition, which, by inducing the accumulation and aggregation of misfolded or unfolded proteins, can lead to endoplasmic reticulum (ER) stress. Accordingly, it was shown that Amblyomin-X, a Kunitz-type inhibitor identified in the transcriptome of the Amblyomma cajennense tick by ESTs sequence analysis of a cDNA library, obtained in recombinant protein form, induces apoptosis in murine renal adenocarcinoma (RENCA) cells by: inducing imbalance between pro- and anti-apoptotic Bcl-2 family proteins, dysfunction/mitochondrial damage, production of reactive oxygen species (ROS), caspase cascade activation, and proteasome inhibition, all ER-stress inductive. Moreover, there was no manifest action on normal mouse-fibroblast cells (NHI3T3), suggesting an Amblyomin-X tumor-cell selectivity. Taken together, these evidences indicate that Amblyomin-X could be a promising candidate for cancer therapy.

The Effects of Lipoic Acid on Yolk Nutrient Utilization, Energy Metabolism, and Redox Balance over Time in Artemia sp.

Lipoic acid (LA) is a mitochondrial coenzyme that, depending on the concentration and exposure time, can behave as an antioxidant or pro-oxidant agent and has a proven ability to modulate metabolism by promoting lipid and glucose oxidation for energy production. To assess the effects of LA on energy metabolism and redox balance over time, Artemia sp. nauplii was used as an animal model. The administered concentrations of the antioxidant were 0.05, 0.1, 0.5, 1.0, 5.0, and 10.0 µM. Therefore, possible differences in protein, triglyceride, glucose, and lactate concentrations in the artemia samples and total ammoniacal nitrogen (TAN) in the culture water were evaluated. We also measured the effects of LA on in vivo activity of the electron transport system (ETS), antioxidant capacity, and production of reactive oxygen species (ROS) at 6, 12, 18, and 24 h post-hatching. There was a decrease in glucose concentration in the LA-treated animals, and a decrease in ammonia production was observed in the 0.5 µM LA treatment. ETS activity was positively regulated by the addition of LA, with the most significant effects at concentrations of 5.0 and 10.0 µM at 12 and 24 h. For ETS activity, treatments with LA presented the highest values at 24 h, a period when ROS production decreased significantly, for the treatment with 10.0 µM. LA showed positive regulation of energy metabolism together with a decrease in ROS and TAN excretion.

Integrating the autoimmune connective tissue diseases for the medical student: A classification proposal based on pathogenesis and clinical phenotype.

It is hard for medical students to recognize and understand the clinical presentation of systemic connective tissue diseases (SCTDs). In this study, we aimed to review the immune mechanisms of the main SCTDs and to propose a classification system focused on the student and based on each immune dysfunction's clinical phenotype. The search involved the MEDLINE database and included the terms "systemic lupus erythematosus," "antiphospholipid syndrome," "inflammatory myopathies," "rheumatoid arthritis," "Sjögren's syndrome" or "systemic sclerosis" and "pathogenesis," and "immunology" or "mechanism of disease." Systemic lupus erythematosus (SLE) is a prototypic immune-complex disease with a tendency toward vascular injury. Antiphospholipid syndrome (APS) is a diffuse immune-mediated thrombotic vasculopathy. In inflammatory myopathies (IMs), muscle inflammation leading to muscle weakness is the cardinal manifestation. Rheumatoid arthritis (RA) is a unique form of erosive and destructive polyarthritis. Sjögren's syndrome (SS) causes sicca symptoms due to infiltration of the exocrine glands. Disseminated fibrosis in systemic sclerosis (SSc) is caused by vascular injury with excessive fibroblast activation. After the review, we created a focus group involving all the authors to group the diseases according to their pathogenesis and clinical phenotype. Our group agreed that SCTDs can be divided in 3 groups based on the preferential clinical presentation and immune dysfunction: 1) vasculopathic features (SLE and APS), 2) tissue inflammation (IMs, RA, and SS), and 3) tissue fibrosis (SSc). In synthesis, we suggest that clustering SCTDs in groups based on clinical phenotype and presumptive immune dysfunction instead of ordering autoantibodies randomly can help students understand the diseases.

Peripheral Neuropathy in Systemic Autoimmune Rheumatic Diseases-Diagnosis and Treatment.

Peripheral neuropathy (PN) is frequently observed in systemic rheumatic diseases and is a challenge in clinical practice. We aimed to review the evidence on the subject and proposed a comprehensive approach to these patients, facilitating diagnosis and management. We searched the MEDLINE database for the terms (and its respective Medical Subject Headings (MeSH) terms): "peripheral neuropathy" AND "rheumatic diseases" OR "systemic lupus erythematosus", "rheumatoid arthritis", "Sjogren syndrome", and "vasculitis" from 2000 to 2023. This literature review focuses on the diagnostic workup of PNs related to systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, and systemic vasculitis. For every type of PN, we provide a pragmatic flowchart for diagnosis and also describe evidence-based strategies of treatment.

Emotional, hyperactivity and inattention problems in adolescents with immunocompromising chronic diseases during the COVID-19 pandemic.

OBJECTIVE: To assess factors associated with emotional changes and Hyperactivity/Inattention (HI) motivated by COVID-19 quarantine in adolescents with immunocompromising diseases. METHODS: A cross-sectional study included 343 adolescents with immunocompromising diseases and 108 healthy adolescents. Online questionnaires were answered including socio-demographic data and self-rated healthcare routine during COVID-19 quarantine and validated surveys: Strengths and Difficulties Questionnaire (SDQ), Pittsburgh Sleep Quality Index (PSQI), Pediatric Quality of Life Inventory 4.0 (PedsQL4.0). RESULTS: The frequencies of abnormal emotional SDQ scores from adolescents with chronic diseases were similar to those of healthy subjects (110/343 [32%] vs. 38/108 [35%], p = 0.548), as well as abnormal hyperactivity/inattention SDQ scores (79/343 [23%] vs. 29/108 [27%], p = 0.417). Logistic regression analysis of independent variables associated with abnormal emotional scores from adolescents with chronic diseases showed: female sex (Odds Ratio [OR = 3.76]; 95% Confidence Interval (95% CI) 2.00‒7.05; p < 0.001), poor sleep quality (OR = 2.05; 95% CI 1.08‒3.88; p = 0.028) and intrafamilial violence during pandemic (OR = 2.17; 95% CI 1.12‒4.19; p = 0.021) as independently associated with abnormal emotional scores, whereas total PedsQL score was inversely associated with abnormal emotional scores (OR = 0.95; 95% CI 0.93‒0.96; p < 0.0001). Logistic regression analysis associated with abnormal HI scores from patients evidenced that total PedsQL score (OR = 0.97; 95% CI 0.95‒0.99; p = 0.010], changes in medical appointments during the pandemic (OR = 0.39; 95% CI 0.19-0.79; p = 0.021), and reliable COVID-19 information (OR = 0.35; 95% CI 0.16‒0.77; p = 0.026) remained inversely associated with abnormal HI scores. CONCLUSION: The present study showed emotional and HI disturbances in adolescents with chronic immunosuppressive diseases during the COVID-19 pandemic. It reinforces the need to promptly implement a longitudinal program to protect the mental health of adolescents with and without chronic illnesses during future pandemics.

Physical exercise for dermatomyositis and polymyositis: a systematic review and meta-analysis.

Trials regarding physical exercise in dermatomyositis (DM) and polymyositis (PM) are heterogeneous. We aimed to summarize and critically analyze the available evidence to support the hypothesis that exercise is safe and improves strength and aerobic capacity. We performed a systematic review of clinical trials regarding physical exercise in dermatomyositis and polymyositis, without time restriction. We included studies from MEDLINE, EMBASE, SciELO, and Web of Science, published in English, Portuguese, or Spanish, and reporting outcomes related to safety, muscle performance, or aerobic capacity. The certainty of evidence was evaluated in accordance with the GRADE methodology. Meta-analysis was carried using pooled standardized mean differences (SMD) with 95% confidence interval as effect measure. We included 19 studies and 298 patients. The certainty of evidence was downgraded due to unbalanced confounding variables. The meta-analysis demonstrated improvements in strength (SMD [95% CI] = 0.61 [0.37-0.85], P < .00001) and aerobic capacity (SMD [95% CI] = 0.82 [0.29-1.34], P = .002), with no difference in creatine phosphokinase levels (SMD [95% CI] = - 0.23 [- 0.5-0.03], P = .08) after the interventions. No exacerbation was reported, and results were favorable in all stages of disease and ages, but might be different in the future with new classification criteria for PM and the inclusion of other idiopathic inflammatory myopathies. Novel approaches such as blood flow restriction training and aquatic plyometric exercises were promising. Physical exercise in DM/PM patients of all ages is probably safe and moderately improves muscle strength and aerobic capacity.

Comprehensive Characterization of the Regulatory Landscape of Adrenocortical Carcinoma: Novel Transcription Factors and Targets Associated with Prognosis.

We reconstructed a transcriptional regulatory network for adrenocortical carcinoma (ACC) using transcriptomic and clinical data from The Cancer Genome Atlas (TCGA)-ACC cohort. We investigated the association of transcriptional regulatory units (regulons) with overall survival, molecular phenotypes, and immune signatures. We annotated the ACC regulons with cancer hallmarks and assessed single sample regulon activities in the European Network for the Study of Adrenal Tumors (ENSAT) cohort. We found 369 regulons associated with overall survival and subdivided them into four clusters: RC1 and RC2, associated with good prognosis, and RC3 and RC4, associated with worse outcomes. The RC1 and RC3 regulons were highly correlated with the 'Steroid Phenotype,' while the RC2 and RC4 regulons were highly correlated with a molecular proliferation signature. We selected two regulons, NR5A1 (steroidogenic factor 1, SF-1) and CENPA (Centromeric Protein A), that were consistently associated with overall survival for further downstream analyses. The CENPA regulon was the primary regulator of MKI-67 (a marker of proliferation KI-67), while the NR5A1 regulon is a well-described transcription factor (TF) in ACC tumorigenesis. We also found that the ZBTB4 (Zinc finger and BTB domain-containing protein 4) regulon, which is negatively associated with CENPA in our transcriptional regulatory network, is also a druggable anti-tumorigenic TF. We anticipate that the ACC regulons may be used as a reference for further investigations concerning the complex molecular interactions in ACC tumors.

Hydrothermally-altered feldspar reduces metal toxicity and promotes plant growth in highly metal-contaminated soils.

Novel green technologies for soil remediation have been focusing on altering soil properties and improving soil health. Hydrothermally-altered feldspar (HYP, HydroPotash), recently developed, is being related as both an efficient amendment to immobilize heavy metals in soils and a plant nutrients source, consisting in a promising technology for revegetation of contaminated sites. In order to evaluate the effectiveness of using HYP for phytostabilization programs, two different soils (Technosol and Oxisol) collected from a smelting site were amended with increasing doses of HYPs (HYP-1 and HYP-2): 15, 30, 60, and 120 Mg ha-1. For comparison, a control (soil without amendment) and a soil amended with zeolite (clinoptilolite) were also included as treatments. After 90 days of incubation, HYPs decreased up to 83.8 % of Cd availability and reduced exchangeable Al up to 100 %. HydroPotash increased pH, cation exchange capacity, and contents of potassium, calcium, and phosphorus, as well as microbial biomass carbon, and fluorescein diacetate hydrolysis of soils. Andropogon gayanus, Eucalyptus grandis, and Heterocondylus vitalbae started growing from the dose of 15 Mg ha-1 HYPs in the Oxisol and 60 Mg ha-1 HYPs in the Technosol. Principal component analysis indicates that plant shoot dry weight was negatively correlated with extractable Cd and Zn and positively with pH, CEC, and Ca content. Besides promoting plant growth, HYPs reduced heavy metals (Cd and Zn) absorption by plants, indicating that HYP has potential use as an amendment in phytostabilization programs.

Pycard and BC017158 Candidate Genes of Irm1 Locus Modulate Inflammasome Activation for IL-1ß Production.

We identified Pycard and BC017158 genes as putative effectors of the Quantitative Trait locus (QTL) that we mapped at distal chromosome 7 named Irm1 for Inflammatory response modulator 1, controlling acute inflammatory response (AIR) and the production of IL-1ß, dependent on the activation of the NLRP3 inflammasome. We obtained the mapping through genome-wide linkage analysis of Single Nucleotide Polymorphisms (SNPs) in a cross between High (AIRmax) and Low (AIRmin) responder mouse lines that we produced by several generations of bidirectional selection for Acute Inflammatory Response. A highly significant linkage signal (LOD score peak of 72) for ex vivo IL-1ß production limited a 4 Mbp interval to chromosome 7. Sequencing of the locus region revealed 14 SNPs between "High" and "Low" responders that narrowed the locus to a 420 Kb interval. Variants were detected in non-coding regions of Itgam, Rgs10 and BC017158 genes and at the first exon of Pycard gene, resulting in an E19K substitution in the protein ASC (apoptosis associated speck-like protein containing a CARD) an adaptor molecule in the inflammasome complex. Silencing of BC017158 inhibited IL1-ß production by stimulated macrophages and the E19K ASC mutation carried by AIRmin mice impaired the ex vivo IL-1ß response and the formation of ASC specks in stimulated cells. IL-1ß and ASC specks play major roles in inflammatory reactions and in inflammation-related diseases. Our results delineate a novel genetic factor and a molecular mechanism affecting the acute inflammatory response.

Lonomia obliqua Venom Induces NF-κB Activation and a Pro-Inflammatory Profile in THP-1-Derived Macrophage.

Envenomation caused by contact with Lonomia obliqua bristles is characterized by pain, an intense systemic proinflammatory reaction and disturbances in the coagulation cascade that can cause severe clinical manifestations and death. However, the role of immune system components in these effects is still poorly understood. In this study, we evaluated the cytotoxic effect of L. obliqua venom on THP-1-derived macrophages and its ability to modulate inflammatory markers, as well as the cytokine and chemokine release profile. Our results show that L. obliqua venom is able to directly exert a potent pro-inflammatory reaction in macrophages, characterized by the activation of the NF-κB transcription factor pathway, the expression of CD80 and CD83, and the release of pro-inflammatory mediators such as TNF-α, IL-1ß, IL-6, IL-8 and CXCL10. These results suggest that macrophages can play an important role during the orchestration of the inflammatory response present in envenomation caused by Lonomia obliqua caterpillars.