Dataset Information

Effects of Gasdermin D in Modulating Murine Lupus and its Associated Organ Damage.

ABSTRACT:

Objective

Gasdermin D (GSDMD) is the key executioner of an inflammatory cell death mechanism known as pyroptosis. Recent reports have also implicated GSDMD in other mechanisms of cell death, including apoptosis, necroptosis, and NETosis. Given the role of dysregulated cell death in autoimmune syndromes such as systemic lupus erythematosus (SLE), this study was undertaken in a murine lupus model to investigate whether GSDMD plays a pathogenic role in systemic autoimmunity by promoting inflammatory cell death, leading to increased generation of nuclear autoantigens and autoantibodies.

Methods

An imiquimod-induced model of SLE was tested in GSDMD^-/- mice (n = 30), with wild-type (WT) mice as controls (n = 34), on a C57BL/6 background. At the time of euthanasia, the mice were examined for serum autoantibodies, immune complex deposition, organ inflammation, immune dysregulation, and type I interferon responses. A model of pristane-induced lung injury in GSDMD^-/- mice (n = 7), with WT mice as controls (n = 10), was used to confirm the pulmonary phenotype. Regulation of various mechanisms of cell death by GSDMD was investigated in the mice.

Results

Unexpectedly, GSDMD^-/- mice developed enhanced mortality, more severe renal and pulmonary inflammation, and exacerbated autoantibody production in response to imiquimod. Pulmonary involvement was also more severe in the absence of GSDMD in mice with pristane-induced lung injury. Compared to WT mice, lack of GSDMD was associated with increased levels of circulating nuclear autoantigens (P < 0.01), anti-double-stranded DNA autoantibodies (P < 0.01), tissue immune complex deposition (P < 0.05), expansion of myeloid cell subsets (P < 0.05), and enhanced B cell activation and plasma cell differentiation (P = 0.001). Moreover, in the absence of GSDMD, enhanced autoantigen generation was associated with increased local induction of cell death in vivo.

Conclusion

GSDMD negatively regulates autoantigen generation and immune dysregulation in response to tissue injury and may play previously unappreciated protective roles in systemic autoimmunity.

SUBMITTER: Wang X

PROVIDER: S-EPMC8498992 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effects of Gasdermin D in Modulating Murine Lupus and its Associated Organ Damage.

Wang Xinghao X Blanco Luz P LP Carmona-Rivera Carmelo C Nakabo Shuichiro S Pedersen Hege L HL Yu Zu-Xi ZX Kaplan Mariana J MJ

Arthritis & rheumatology (Hoboken, N.J.) 20201017 12

<h4>Objective</h4>Gasdermin D (GSDMD) is the key executioner of an inflammatory cell death mechanism known as pyroptosis. Recent reports have also implicated GSDMD in other mechanisms of cell death, including apoptosis, necroptosis, and NETosis. Given the role of dysregulated cell death in autoimmune syndromes such as systemic lupus erythematosus (SLE), this study was undertaken in a murine lupus model to investigate whether GSDMD plays a pathogenic role in systemic autoimmunity by promoting inf ...[more]

PMID: 32692482

Similar Datasets

Project description:BackgroundSystemic lupus erythematosus (SLE) can affect a plethora of organ systems and cause organ damage due to the disease process and medication toxicity, notably corticosteroids. Patients with SLE often suffer irreversible organ damage. Older age, glucocorticoid use, longer disease duration, and disease activity all represent risk factors for organ damage. This study aims to assess the incidence and predictors of organ damage among Saudi Arabian SLE patients.MethodsThis study is a single-center, retrospective cohort observational study conducted at the adult Rheumatology Outpatient Clinic in King Fahad Medical City, Riyadh, Saudi Arabia. It included all patients aged 16 years and older who met at least four of the American College of Rheumatology Classification criteria for SLE or had a renal biopsy consistent with lupus nephritis and had regular follow-ups at our hospital, with the last visit occurring within 2 years.ResultsThe study included 196 patients with SLE, predominantly female (92.9%) with a mean age of 36.2 years and an average disease duration of 8.88 years. Among the patients, 38.8% had a positive Systemic Damage Index (SDI) score. Hydroxychloroquine was used by 93.4% of the patients, and 46.9% had a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 3 or higher. The neuropsychiatric system was most affected, with 16.8% of patients having positive SDI scores in this domain, followed by the renal system at 9.2%. Patients with positive SDI scores were significantly older, had longer disease duration, and had higher prevalence of diabetes mellitus and hypertension.ConclusionTo address organ damage in SLE patients, integrating adjunctive therapies like antihypertensives and antidiabetic agents into management plans is essential. Future research should adopt prospective cohort designs to evaluate the dynamic interactions between comorbidities and organ damage over time. Additionally, studies should assess the effectiveness of combined treatment strategies and develop targeted approaches for high-risk groups to enhance outcomes and quality of life.

Project description:IntroductionApproximately 33-50% of patients with systemic lupus erythematosus (SLE) develop organ damage within 5 years of diagnosis. Real-world studies that capture the healthcare resource utilization (HCRU) and costs associated with SLE-related organ damage are limited. The aim of this study was to evaluate HCRU and costs associated with organ damage in patients with SLE in the USA.MethodsThis retrospective study (GSK study 208380) used the PharMetrics Plus administrative claims database from 1 January 2008 to 30 June 2019. Patients with SLE and organ damage were identified using International Classification of Diseases (ICD)-9/10 codes derived from the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. The first observed diagnosis of organ damage was designated as the index date. Selection criteria included: ≥18 years of age; ≥1 inpatient or ≥2 outpatient claims for SLE (≥30 days apart before the index date; ICD-9: 710.0 or ICD-10: M32, excluding M32.0); ≥1 inpatient or ≥3 outpatient claims for organ damage within 6 months for the same organ system code; continuous enrollment of 12 months both pre- and post-index date. The proportion of patients with new organ damage, disease severity, SLE flares, SLE-related medication patterns, HCRU and all-cause costs (2018 US$) were assessed 12 months pre- and post-index date.ResultsOf the 360,803 patients with a diagnosis of SLE, 8952 patients met the inclusion criteria for the presence of new organ damage. Mean (standard deviation (SD)) age was 46.4 (12.2) years and 92% of patients were female. The most common sites of organ damage were neuropsychiatric (22.0%), ocular (12.9%), and cardiovascular (11.4%). Disease severity and proportion of moderate/severe flare episodes significantly increased from pre- to post-index date (p < 0.0001). Overall, SLE-related medication patterns were similar pre- versus post-index date. Inpatient, emergency department and outpatient claims increased from pre- to post-index date and mean (SD) all-cause costs were 71% higher post- versus pre-index date ($26,998 [57,982] vs $15,746 [29,637], respectively).ConclusionsThe economic impact associated with organ damage in patients with SLE is profound and reducing or preventing organ damage will be pivotal in alleviating the burden for patients and healthcare providers.

Dataset Information

Effects of Gasdermin D in Modulating Murine Lupus and its Associated Organ Damage.

Objective

Methods

Results

Conclusion

Publications

Effects of Gasdermin D in Modulating Murine Lupus and its Associated Organ Damage.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets