Objective
Development of proteinuria in lupus nephritis (LN) is associated with podocyte dysfunction. The NLRP3 inflammasome has been implicated in the pathogenesis of LN. The purpose of this study ...was to investigate whether NLRP3 inflammasome activation is involved in the development of podocyte injury in LN.
Methods
A fluorescence‐labeled caspase 1 inhibitor probe was used to detect the activation of NLRP3 inflammasomes in podocytes derived from lupus‐prone NZM2328 mice and from renal biopsy tissues obtained from patients with LN. MCC950, a selective inhibitor of NLRP3, was used to treat NZM2328 mice. Proteinuria, podocyte ultrastructure, and renal pathology were evaluated. In vitro, sera from diseased NZM2328 mice were used to stimulate a podocyte cell line, and the cells were analyzed by flow cytometry.
Results
NLRP3 inflammasomes were activated in podocytes from lupus‐prone mice and from patients with LN. Inhibition of NLRP3 with MCC950 ameliorated proteinuria, renal histologic lesions, and podocyte foot process effacement in lupus‐prone mice. In vitro, sera from diseased NZM2328 mice activated NLRP3 inflammasomes in the podocyte cell line through the production of reactive oxygen species.
Conclusion
NLRP3 inflammasomes were activated in podocytes from lupus‐prone mice and from LN patients. Activation of NLRP3 is involved in the pathogenesis of podocyte injuries and the development of proteinuria in LN.
RIP3 activation leads to activation of necroptosis and the NLRP3 inflammasome pathways. The activation of RIP3 in lupus nephritis (LN) has not been investigated. In this study, RIP3 and necroptosis ...pathway activations were demonstrated in podocytes in renal biopsies from patients with class IV LN and in the diseased kidneys from lupus-prone NZM2328 and MRL/lpr mice. RIP3 activation was accompanied with the activation of MLKL, the effector molecule of the necroptosis pathway, and activation of caspase-1, the effector of the NLRP3 inflammasome pathway. Podocyte activation of RIP3 was detected readily with the development of LN in NZM2328 mice, suggesting this activation may play a significant role in the pathogenesis of LN. GSK872, a RIP3 specific inhibitor, inhibited the development of LN in MRL/lpr mice with down-regulation of RIP3 activation in podocytes, decreased the splenic sizes and weights and anti-dsDNA antibody titers. IgG from pooled sera of diseased NZM2328 mice succumbing to LN induced both the necroptosis pathway and NLRP3 inflammasome activation in a podocyte cell line and this activation was specifically blocked by GSK872. These results indicate that the necroptosis pathway and the RIP3 dependent NLRP3 inflammasome pathway are activated in podocytes during LN. Inhibition of RIP3 kinase may be a novel therapeutic approach to treat LN and systemic lupus erythematosus (SLE).
•Necroptosis and NLRP3 inflammasome pathways are activated in podocytes in LN.•RIP3 regulates both NLRP3 inflammasome and necroptosis activation.•IgG from LN activates RIP3 dependent necroptosis and NLRP3 inflammasome pathways.•Inhibition of RIP3 reduces autoimmunity and alleviates clinical manifestation of LN.
PURPOSE OF REVIEWA combination of systemic autoimmunity and tissue response to immune injury underlie renal involvement in lupus erythematosus. In this review, we discuss recent literature ...investigating pathogenetic mechanisms of lupus glomerulonephritis.
RECENT FINDINGSIn lupus glomerulonephritis, glomerular immune complexes were believed to be the primary mediators of renal disease. Recent studies make it apparent that autoantibodies of multiple specificities participate in the formation of immune complexes, deposited in the kidneys. Renal infiltration by T cells, macrophages, and dendritic cells have a dominant role in the progression of lupus glomerulonephritis leading to renal failure. Activation of Toll-like receptors modulates autoantibody production and systemic interferon responses. However, glomerular cell responses to immune injury influence disease outcome. In addition, new insights on the genetics of susceptibility to end-organ damage in lupus glomerulonephritis have been discovered. Differential glomerular responses reflected in gene expression profiles during disease progression provide potential markers for diagnosis of lupus glomerulonephritis progression and flares. In addition, studies of end-organ responses provide new targets for therapeutic interventions.
SUMMARYLupus glomerulonephritis is a prototype of immune complex disease mediated by autoantibodies of multiple specificities, one of which is anti-DNA. Murine models of spontaneous systemic lupus erythematosus have been critical for understanding the underlying disease. Recent studies demonstrate that in addition to systemic autoimmunity, end-organ responses, and end-organ resistance to damage are also critical in determining disease outcome. This understanding should influence design of novel therapeutic approaches in systemic lupus erythematosus.
A brother and sister developed a previously undescribed constellation of autoimmune manifestations within their first year of life, with uncontrollable bullous pemphigoid, colitis, and proteinuria. ...The boy had hemophilia due to a factor VIII autoantibody and nephrotic syndrome. Both children required allogeneic hematopoietic cell transplantation (HCT), which resolved their autoimmunity. The early onset, severity, and distinctive findings suggested a single gene disorder underlying the phenotype. Whole-exome sequencing performed on five family members revealed the affected siblings to be compound heterozygous for two unique missense mutations in the 70-kD T cell receptor ζ-chain associated protein (ZAP-70). Healthy relatives were heterozygous mutation carriers. Although pre-HCT patient T cells were not available, mutation effects were determined using transfected cell lines and peripheral blood from carriers and controls. Mutation R192W in the C-SH2 domain exhibited reduced binding to phosphorylated ζ-chain, whereas mutation R360P in the N lobe of the catalytic domain disrupted an autoinhibitory mechanism, producing a weakly hyperactive ZAP-70 protein. Although human ZAP-70 deficiency can have dysregulated T cells, and autoreactive mouse thymocytes with weak Zap-70 signaling can escape tolerance, our patients' combination of hypomorphic and activating mutations suggested a new disease mechanism and produced previously undescribed human ZAP-70-associated autoimmune disease.
Inflammation plays a key role in the pathogenesis of lupus nephritis (LN) and inflammatory cytokines within the glomeruli are critical in this process. However, little information is available for ...the identities of the cell types that are primarily responsible for the production and function of the various cytokines. We have devised a novel method to visualize cytokine signals in the kidney by confocal microscopy and found that cytokine production within the glomerulus is cell type-specific and under translational control. In the lupus-prone NZM2328 mice with chronic glomerulonephritis, IL-6, IL-1β, and TNF-α in the glomerulus were produced predominantly by mesangial cells, podocytes, and glomerulus-infiltrating blood-derived macrophages, respectively. Microarray and RNASeq analyses showed that these cells expressed the receptors for these cytokines. Together the 3 cell types form a cytokine circuit in amplifying cytokine responses in LN. The intrinsic cells and infiltrating macrophages also produced other cytokines including M-CSF, SCF, and IL-34 that constituted within the enclosed glomerular space the soluble effector milieu which may mediate cellular damage and proliferation, and cytokine transcriptional and translation regulation. IL-10 and IL-1β were translationally regulated in the glomeruli in the intact kidney in a cell type-specific manner. The production of these 2 cytokines by infiltrating macrophages was undetectable in a visualization system for in situ protein accumulation despite high mRNA expression levels. However, these macrophages in isolated glomeruli which are released from Bowman's capsules produced large amounts of IL-10 and IL-1β. These data reveal the complexity of cytokine regulation, production, and function in the glomerulus and provide a model in which cytokine blocking may be beneficial in LN treatment.
•An in situ cytokine detection method was used to visualize cytokines in glomeruli.•Cell-specific cytokine circuit of TNF-α, IL-6 and IL-1β production in LN was found.•Mesangial cells, podocytes and macrophages express receptors for the interactions.•Mesangial cell and podocyte produced M-CSF and SCF, and IL-34 respectively in cGN.•The glomerulus microenvironment mediates cytokine translational regulation in LN.
Abstract Using data of 200, 522, 572, and 287 Chinese from Australia, China, Hong Kong and Taiwan respectively, this study aimed at comparing the mental health literacy of Chinese people from ...different communities, and between Chinese communities and the Australian general public. The participants were asked questions that assessed their recognition of depression and schizophrenia. Compared with the Australians, much lower percentages of Chinese in the four Chinese communities could correctly identify depression and early schizophrenia. Commonalities in the preference for ‘psychiatrist’, ‘psychologist’, ‘Chinese medical doctor’, and ‘Chinese traditional healer’, a lack of knowledge of medications, and a higher likelihood of endorsement of traditional Chinese medicines were found among the four Chinese communities. Differences in the preference for ‘general practitioner’ and ‘social worker’, and a higher percentage of endorsement of herbal medicines were observed among the different Chinese communities. Cultural factors such as Chinese perceptions of mental illness, and socio-contextual factors such as differences in mental health care system in the four communities were offered to explain these commonalities and differences. Mental health promotion programmes for Chinese people may need to consider the above-mentioned cultural and socio-contextual factors so that specific promotion programmes can be developed.
Background:
Few studies have been performed to explore mental health literacy and stigmatising attitudes towards mental illness and their relationships with causal beliefs about mental illness among ...Chinese people in Taiwan.
Aims:
Using a comparative approach, this study attempted to compare the mental health literacy and stigmatising attitudes of Taiwanese Chinese with those found among Australian and Japanese participants in other studies and to explore how mental health literacy and stigmatising attitudes relate to different perceptions of causes of mental illness.
Methods:
A convenience sample of 287 participants completed a battery of standardised questionnaires.
Results:
A much lower percentage of Taiwanese people than Australians could correctly identify depression and schizophrenia. The Taiwanese respondents rated psychiatrists and clinical psychologists as more helpful than social workers and general practitioners (GPs) and expressed more uncertainty about the usefulness of certain medications when compared to the Australian and Japanese samples. Interestingly, Taiwanese Chinese hold similarly high levels of stigma towards schizophrenia, but lower levels of stigma towards depression when compared to the Japanese respondents. Taiwanese respondents who have higher levels of mental health literacy about schizophrenia were less willing to interact with people with schizophrenia than those with lower levels of mental health literacy.
Conclusion:
This study underlines the need for public education programmes to improve knowledge of various mental illnesses and to reduce stigmatising attitudes among Taiwanese Chinese. The aforementioned socially and culturally driven beliefs must be taken into consideration so that culturally relevant education programmes can be developed.
Abstract Myeloid-derived suppressor cells (MDSC) and Th17 cells were found to expand in collagen-induced arthritis (CIA) significantly. Two subsets of MDSC, polymorphonuclear (PMN) and mononuclear ...(MO), were detected and their ratios varied during the development of CIA. The depletion of MDSC in vivo resulted in suppression of T-cell proliferation and decreased IL-17A and IL-1β production. The adoptive transfer of MDSC restored the severity of arthritis and Th17 cell differentiation. The depletion of MDSCs on day 35 resulted in arthritis amelioration without reaching a significant difference. Furthermore, MDSCs from CIA mice had higher production of IL-1β and promoted Th17 cell differentiation. The expansion of MDSCs in the peripheral blood of rheumatoid arthritis (RA) patients was in correlation with increased Th17 cells and disease activity DAS28. These results support the hypothesis that MDSC may play a significant proinflammatory role in the pathogenesis of CIA and RA by inducing Th17 development in an IL-1β-dependent manner.
Highlights • GWA studies that identify candidate genes in human lupus are summarized. • Examples of the identification of candidate genes are provided. • Human and murine genes conferring end organ ...resistance to damage are discussed.
Abstract Dendritic cells (DC) mediate airway Ag presentation and play key roles in asthma and infections. Although DC subsets are known to perform different functions, their occurrence in mouse lungs ...has not been clearly defined. In this study, three major lung DC populations have been found. Two of them are the myeloid and plasmacytoid DC (PDC) well-characterized in other lymphoid organs. The third and largest DC population is the integrin αE (CD103) β7-positive and I-AhighCD11chigh-DC population. This population was found to reside in the lung mucosa and the vascular wall, express a wide variety of adhesion and costimulation molecules, endocytose avidly, present Ag efficiently, and produce IL-12. Integrin αEβ7+ DC (αE-DC) were distinct from intraepithelial lymphocytes and distinguishable from CD11bhigh myeloid and mPDCA-1+B220+Gr-1+ PDC populations in surface marker phenotype, cellular functions, and tissue localization. Importantly, this epithelial DC population expressed high levels of the Langerhans cell marker Langerin and the tight junction proteins Claudin-1, Claudin-7, and ZO-2. In mice with induced airway hyperresponsiveness and eosinophilia, αE-DC numbers were increased in lungs, and their costimulation and adhesion molecules were up-regulated. These studies show that αE-DC is a major and distinct lung DC population and a prime candidate APC with the requisite surface proteins for migrating across the airway epithelia for Ag and pathogen capture, transport, and presentation. They exhibit an activated phenotype in allergen-induced lung inflammation and may play significant roles in asthma pathogenesis.
PDF
