scholarly journals Pathological manifestation of autoimmune myocarditis is detected prior to glomerulonephritis in a murine model of lupus nephritis

Lupus ◽  
2020 ◽  
Vol 29 (13) ◽  
pp. 1790-1799
Author(s):  
Nicholas A Young ◽  
Kyle Jablonski ◽  
Emmy Schwarz ◽  
Ifeoma Okafor ◽  
Jeffrey Hampton ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Cardiac Tissue ◽  
Myocardial Edema ◽  
Histopathological Analysis ◽  
Autoimmune Myocarditis ◽  
Murine Lupus ◽  
Tnf Α ◽  
Pathological Manifestation ◽  
Lupus Disease Activity

Objective Since enhanced cardiac magnetic resonance imaging (cMRI) signals have been associated with lupus disease activity in humans prior to renal failure and novel, cardiac-focused therapeutic strategies could be investigated with an associated animal model, autoimmune myocarditis was characterized in murine lupus nephritis (NZM2410). Methods Weekly blood urea nitrogen (BUN) levels and weights were recorded. Cardiac function was assessed by echocardiogram. Myocardial edema was measured with quantitative T2 cMRI mapping. Endpoint serum and cardiac tissue were collected for histopathological analysis and cytokine measurements. Results Despite showing no signs of significant renal disease, mice displayed evidence of myocarditis and fibrosis histologically at 30–35 weeks. Moreover, T2 cMRI mapping displayed robust signals and analysis of sagittal heart sections showed significant myocardium thickening. Cytokine expression levels of IL-2, IL-10, TNF-α, CXCL1, and IL-6 were significantly enhanced in serum. Echocardiograms demonstrated significantly increased ventricular diameters and reduced ejection fractions, while immunohistochemical staining identified CD4+ and CD8+ T cells, and IL-17 in cardiac infiltrates. Human lupus cardiac tissue showed similar histopathology with enhanced infiltrates by H&E, fibrosis, and CD4+ detection. Conclusions Histopathology, functional abnormalities, and enhanced cMRI signals indicative of myocarditis are detected in NZM2410 mice without glomerulonephritis, which supports the primary pathological role of autoimmune-mediated, cardiac-targeted inflammation in lupus.

scholarly journals The role of aldosterone blockade in murine lupus nephritis

2008 ◽  
Vol 10 (1) ◽  
pp. R5 ◽  
Author(s):  
Seetha U Monrad ◽  
Paul D Killen ◽  
Marc R Anderson ◽  
Amanda Bradke ◽  
Mariana J Kaplan
Keyword(s):  
Lupus Nephritis ◽  
Murine Lupus ◽  
Aldosterone Blockade

scholarly journals The Long Pentraxin PTX3 Controls Klebsiella Pneumoniae Severe Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Fatemeh Asgari ◽  
Domenico Supino ◽  
Raffaella Parente ◽  
Nadia Polentarutti ◽  
Matteo Stravalaci ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Klebsiella Pneumoniae ◽  
Inflammatory Responses ◽  
Severe Infection ◽  
Multidrug Resistant ◽  
Histopathological Analysis ◽  
Independent Manner ◽  
Human Sepsis ◽  
Tnf Α

Klebsiella pneumoniae is a common pathogen in human sepsis. The emergence of multidrug-resistant K. pneumoniae strains represents a major clinical challenge in nosocomial and community acquired infections. The long pentraxin PTX3, a key component of humoral innate immunity, is involved in resistance to selected pathogens by promoting opsonophagocytosis. We investigated the relevance of PTX3 in innate immunity against K. pneumoniae infections using Ptx3-/- mice and mouse models of severe K. pneumoniae infections. Local and systemic PTX3 expression was induced following K. pneumoniae pulmonary infection, in association with the up-regulation of TNF-α and IL-1β. PTX3 deficiency in mice was associated with higher bacterial burden and mortality, release of pro-inflammatory cytokines as well as IL-10 in the lung and systemically. The analysis of the mechanisms responsible of PTX3-dependent control of K. pneumoniae infection revealed that PTX3 did not interact with K. pneumoniae, or promote opsonophagocytosis. The comparison of susceptibility of wild-type, Ptx3-/-, C3-/- and Ptx3-/-/C3-/- mice to the infection showed that PTX3 acted in a complement-independent manner. Lung histopathological analysis showed more severe lesions in Ptx3-/- mice with fibrinosuppurative, necrotizing and haemorrhagic bronchopneumonia, associated with increased fibrin deposition in the lung and circulating fibrinogen consumption. These findings indicate that PTX3 contributes to the control of K. pneumoniae infection by modulating inflammatory responses and tissue damage. Thus, this study emphasizes the relevance of the role of PTX3 as regulator of inflammation and orchestrator of tissue repair in innate responses to infections.

TNF-alpha protects from exacerbated autoinflammatory response in mouse model of experimental autoimmune myocarditis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
F Rolski ◽  
K Weglarczyk ◽  
P Pelczar ◽  
M Siedlar ◽  
B Ludewig ◽  
...  
Keyword(s):  
T Cells ◽  
High Dose ◽  
Wild Type ◽  
Autoimmune Myocarditis ◽  
Heart Failure Patients ◽  
Tnf Α ◽  
Intercellular Adhesion Molecules ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Abstract Background Myocarditis is an inflammatory heart disease and heart-specific autoimmunity plays an important role in development and progression of the disease. TNF-α is a potent pro-inflammatory cytokine implicated in pathogenesis in many inflammatory diseases. Unexpectedly, clinical studies showed that high dose anti-TNF-α therapy increased hospitalization and mortality of heart failure patients. Purpose To elucidate the role of TNF-α in heart-specific autoimmunity and in activation of cardiac microvascular endothelial cells in autoimmune response. Methods Experimental autoimmune myocarditis (EAM) was induced in BALB/c mice by immunization with α-myosin heavy chain peptide (α-MyHC) together with complete Freund's adjuvant. Development of myocarditis in the absence of adjuvant was analysed in TCR-M mice, which CD4+ T cells expressed transgenic T cell receptor recognizing α-MyHC. The role of TNF-α was addressed using haploinsufficient Tnf+/−, knockout Tnf−/− and TCR-M x Tnf+/− mice. Effects of antigen-dependent T cell response on cardiac microvascular endothelial cell (cMVEC) activation were assessed by flow cytometry, immunoblotting and leukocyte-endothelium adhesion assay. Inflammatory cells were phenotyped using flow cytometry, cytokine production was measured by ELISA. Results EAM induction resulted in reduced prevalence of myocarditis in Tnf+/− and Tnf−/− comparing wild-type mice at day 21 after disease induction. However, Tnf+/− and Tnf−/− mice that developed myocarditis showed higher severity of the disease than wild-type controls. On the other hand, TCR-M x Tnf+/− mice showed exacerbated myocarditis at age of 2 months and were characterized by increased mortality comparing with TCR-M controls. TCR-M Tnf+/− mice showed increased total number of cardiac infiltrates compared to TCR-M controls, but no difference in myeloid subsets were observed. In contrast, Tnf+/− and Tnf−/− mice showed significantly increased percentage of T effector cells in spleens and blood in both myocarditis models. Stimulation with rTNF-α induced expression of intercellular adhesion molecules (ICAM1, VCAM1 and P-selectin) on cMVECs, which was associated with increased ability to bind leukocytes under shear flow conditions. TNF-α deficiency had, however, no impact on antigen-specific activation and proliferation of T-cells. Medium conditioned of antigen-activated wild-type, Tnf+/− and Tnf−/− CD4+ T cells showed similar cMVEC activation measured by increased expression of intercellular adhesion molecules and binding of leukocytes under shear flow condition. Furthermore, Tnf+/− and Tnf−/m- myeloid cells showed increased production of IL-6. Conclusions Our data suggest that TNF-α protects the heart from excessive autoimmune reaction by suppressing expansion of autoreactive effector T cells. Thus, this study uncovers a cardioprotective role of proinflammatory TNF-α and potentially can explain the deleterious effect of high dose anti-TNF-α therapy in heart failure patients. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The National Science Centre Poland

scholarly journals IL-2 Therapy Diminishes Renal Inflammation and the Activity of Kidney-Infiltrating CD4+ T Cells in Murine Lupus Nephritis

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1234 ◽  
Author(s):  
Angelika Rose ◽  
Caroline von Spee-Mayer ◽  
Lutz Kloke ◽  
Kaiyin Wu ◽  
Anja Kühl ◽  
...  
Keyword(s):  
T Cells ◽  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Murine Lupus ◽  
Renal Inflammation ◽  
Treg Population

An acquired deficiency of interleukin-2 (IL-2) and related disturbances in regulatory T cell (Treg) homeostasis play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Low-dose IL-2 therapy was shown to restore Treg homeostasis in patients with active SLE and its clinical efficacy is currently evaluated in clinical trials. Lupus nephritis (LN), a challenging organ manifestation in SLE, is characterized by the infiltration of pathogenic CD4+ T cells into the inflamed kidney. However, the role of the Treg-IL-2 axis in the pathogenesis of LN and the mode of action of IL-2 therapy in the inflamed kidneys are still poorly understood. Using the (NZB × NZW) F1 mouse model of SLE we studied whether intrarenal Treg are affected by a shortage of IL-2 in comparison with lymphatic organs and whether and how intrarenal T cells and renal inflammation can be influenced by IL-2 therapy. We found that intrarenal Treg show phenotypic signs that are reminiscent of IL-2 deprivation in parallel to a progressive hyperactivity of intrarenal conventional CD4+ T cells (Tcon). Short-term IL-2 treatment of mice with active LN induced an expansion the intrarenal Treg population whereas long-term IL-2 treatment reduced the activity and proliferation of intrarenal Tcon, which was accompanied by a clinical and histological amelioration of LN. The association of these immune pathologies with IL-2 deficiency and their reversibility by IL-2 therapy provides important rationales for an IL-2-based immunotherapy of LN.

Pathological and immunological findings in placentas from pregnant BALB/c mice infected with Neospora caninum at early and late stages of gestation

2011 ◽  
Vol 56 (3) ◽  
Author(s):  
Inmaculada López-Pérez ◽  
Esther Collantes-Fernández ◽  
Silvia Rojo-Montejo ◽  
Vanesa Navarro-Lozano ◽  
Verónica Risco-Castillo ◽  
...  
Keyword(s):  
Neospora Caninum ◽  
Placental Tissue ◽  
Parasite Load ◽  
Late Gestation ◽  
Histopathological Analysis ◽  
Caninum Infection ◽  
Tnf Α ◽  
Ifn Γ ◽  
Late Stages

AbstractNeospora caninum is transmitted from a cow to its foetus by vertical transmission and the timing of infection in gestation is an important factor in determining the disease outcome. Few studies have explored the role of the placenta in the outcome of N. caninum infection during pregnancy. Here, we described the N. caninum presence, parasite load, local immune response, and histopathological lesions at the materno-foetal interface after infection of BALB/c mice at early and late stages of gestation. In mice infected at early gestation, N. caninum DNA was detected in foetoplacentary units 7 days post-infection (PI) and in the placenta, but not in viable foetuses on day 14 PI, indicating that the parasite was multiplying primarily in the placental tissues without reaching the foetus. Moreover, parasite DNA was detected in resorptions, suggesting that foetal death could be a consequence of infection. An increase in IFN-γ, TNF-α and IL-10 expression was observed in N. caninum PCR-positive placentas, which could favour N. caninum foetal transmission and be harmful to both the placenta and the foetus. Histopathological analysis revealed necrosis affecting both the maternal and foetal sides of the placenta. At late gestation, transmission occurred rapidly following infection (day 3 PI), but parasite were rarely found. In addition, an increase in cytokine expression was observed in spleen and placental tissues from infected animals, while a downregulation in IL-4 expression was only observed in the spleen. Finally, necrosis in the placenta was limited to the maternal side, suggesting that the parasite is mainly multiplying in the placental tissue at this stage. Thus, the results of the present study indicate that the placenta may be actively involved in N. caninum pathogenesis.

scholarly journals Identification of a Unique Glomerular Factor X Activator in Murine Lupus Nephritis

1999 ◽  
Vol 10 (11) ◽  
pp. 2332-2341
Author(s):  
SUBODINI PERAMPALAM ◽  
LUOQUAN WANG ◽  
NANCY MYERS-MASON ◽  
JEN NEI YEOW ◽  
NIR STANIETSKY ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Tissue Factor ◽  
Factor Vii ◽  
Factor X ◽  
Fibrin Deposition ◽  
Murine Lupus ◽  
Dense Deposits ◽  
Significant Augmentation ◽  
Immunohistochemical Studies

Abstract. The role of glomerular procoagulant activity (PCA) was studied in mice (MRL/lpr, NZBxWF1, and BXSB) that are known to develop lupus nephritis. In young mice (6 to 8 wk) without renal disease, there was no increase in spontaneous glomerular PCA. In contrast, older (5 to 8 mo) autoimmune mice had significant augmentation in glomerular PCA, coinciding with the histologic appearance of severe glomerulonephritis and renal fibrin deposition. The PCA was characterized as a serine protease that directly activated factor X. This factor X activator is not tissue factor because (1) expression of PCA was not dependent on factor VII; (2) a monoclonal antibody against the factor X activator inhibited glomerular PCA, but not tissue factor; (3) the molecular weight (66 kD) of the activator was different from that of tissue factor; and (4) concanavalin A inhibited tissue factor but not glomerular PCA. Immunohistochemical studies localized the factor X activator to the glomerular mesangium and capillary wall of 4- to 6-moold diseased MRL/lpr mice. Immunogold-labeled antibody bound to the dense deposits, macrophages, and endothelial cells of diseased glomeruli. These studies define the role of a unique glomerular factor X activator in murine lupus nephritis.

Protective role for CCR5 in murine lupus nephritis

2012 ◽  
Vol 302 (11) ◽  
pp. F1503-F1515 ◽  
Author(s):  
Jan-Eric Turner ◽  
Hans-Joachim Paust ◽  
Sabrina B. Bennstein ◽  
Phillip Bramke ◽  
Christian Krebs ◽  
...  
Keyword(s):  
T Cell ◽  
Lupus Nephritis ◽  
Tissue Injury ◽  
Protective Role ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Murine Lupus ◽  
Protein Levels ◽  
Chemokine Receptor Ccr5

Leukocyte infiltration is a characteristic feature of human and experimental lupus nephritis and is closely correlated with loss of renal function. The chemokine receptor CCR5 is expressed on monocyte and T cell subsets and is thought to play an important role in recruiting these cells into inflamed organs. To investigate the functional role of CCR5 in lupus nephritis, CCR5-deficient mice were backcrossed onto the lupus-prone MRL- Faslpr (MRL/lpr) genetic background. Unexpectedly, CCR5−/− MRL/lpr mice developed an aggravated course of lupus nephritis in terms of glomerular tissue injury and albuminuria. Deterioration of the nephritis was associated with an overall increase in mononuclear cell infiltration into the kidney, whereas renal leukocyte subtype balance, systemic T cell response, and autoantibody formation were unaffected by CCR5 deficiency. Renal and systemic protein levels of the CCR5 ligand CCL3, which can also attract leukocytes via its alternate receptor CCR1, were significantly increased in nephritic CCR5−/− MRL/lpr mice. Further studies revealed that the systemic increase in the CCR5/CCR1 ligand is also observed in nonimmune CCR5−/− C57BL/6 mice and that this increase was due to a reduced clearance, rather than an overproduction, of CCL3. Taken together, our data support the hypothesis that CCR5-dependent consumption of its own ligands may act as a negative feedback loop to restrain local chemokine levels within inflamed tissues, thereby limiting inflammatory cell influx.

scholarly journals MicroRNAs Implicated in the Immunopathogenesis of Lupus Nephritis

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Cristen B. Chafin ◽  
Christopher M. Reilly
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Mesangial Cells ◽  
Adaptive Immune Response ◽  
Murine Lupus ◽  
Peripheral Blood Mononuclear ◽  
Small Noncoding Rnas ◽  
Cytokine Milieu

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the deposition of immune complexes due to widespread loss of immune tolerance to nuclear self-antigens. Deposition in the renal glomeruli results in the development of lupus nephritis (LN), the leading cause of morbidity and mortality in SLE. In addition to the well-recognized genetic susceptibility to SLE, disease pathogenesis is influenced by epigenetic regulators such as microRNAs (miRNAs). miRNAs are small, noncoding RNAs that bind to the 3′ untranslated region of target mRNAs resulting in posttranscriptional gene modulation. miRNAs play an important and dynamic role in the activation of innate immune cells and are critical in regulating the adaptive immune response. Immune stimulation and the resulting cytokine milieu alter miRNA expression while miRNAs themselves modify cellular responses to stimulation. Here we examine dysregulated miRNAs implicated in LN pathogenesis from human SLE patients and murine lupus models. The effects of LN-associated miRNAs in the kidney, peripheral blood mononuclear cells, macrophages, mesangial cells, dendritic cells, and splenocytes are discussed. As the role of miRNAs in immunopathogenesis becomes delineated, it is likely that specific miRNAs may serve as targets for therapeutic intervention in the treatment of LN and other pathologies.

The role of neuraminidase 1 (NEU1) in cytokine release by primary mouse mesangial cells and disease outcomes in murine lupus nephritis

Autoimmunity ◽  
2021 ◽  
pp. 1-13
Author(s):  
Jessalyn Rodgers ◽  
Kamala Sundararaj ◽  
Evelyn Bruner ◽  
Bethany Wolf ◽  
Tamara K. Nowling
Keyword(s):  
Lupus Nephritis ◽  
Mesangial Cells ◽  
Cytokine Release ◽  
Murine Lupus ◽  
Disease Outcomes ◽  
Primary Mouse

The effect of adenosine triphosphate on sunitinib-induced cardiac injury in rats

2020 ◽  
Vol 39 (8) ◽  
pp. 1046-1053
Author(s):  
MN Aldemir ◽  
M Simsek ◽  
AV Kara ◽  
F Ozcicek ◽  
R Mammadov ◽  
...  
Keyword(s):  
Cardiac Muscle ◽  
Blood Vessels ◽  
Cardiac Tissue ◽  
Troponin I ◽  
Cardiac Injury ◽  
Nuclear Factor Κb ◽  
Control Group ◽  
Histopathological Analysis ◽  
Cardiac Tissues ◽  
Tnf Α

In this study, we aimed to show the effect of adenosine 5′-triphosphate (ATP) on sunitinib-induced cardiac injury in rats. The rats ( n = 30) were divided equally into three groups as sunitinib group (SG), sunitinib plus ATP group (SAG), and healthy group (HG); 2 mg/kg ATP was injected intraperitoneally (ip) to the SAG group. Same volume normal saline as solvent was administered ip to the other two groups. After 1 h, 25 mg/kg sunitinib was applied orally via catheter to stomach in the SAG and SG groups. This procedure was repeated once daily for 5 weeks. At the end of this period, all animals were sacrificed and their cardiac tissue was removed. Malondialdehyde (MDA), total glutathione (tGSH), tumor necrosis factor α (TNF- α), and nuclear factor κB (NF- κB) levels in rats’ cardiac tissues and troponin I (Tp-I) levels in rats’ blood samples were evaluated. Histopathological analysis was also performed in cardiac tissues of the animals. MDA, TNF- α, NF- κB, and Tp-I levels were higher in the SG group compared to the SAG and HG groups ( p < 0.001). tGSH levels of the SG group were lower than the SAG and HG groups ( p < 0.001). The structure and morphology of cardiac muscle fibers and blood vessels were normal in the control group. In the SG group, obvious cardiac muscle tissue damage with dilated myofibers, locally atrophic myofibers, and congested blood vessels were observed. In the SAG group, marked amelioration in these findings was observed. We showed this for the first time that ATP administration exerts a protective effect against cardiac effects of sunitinib.

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