Early Ovariectomy Results in Reduced Numbers of CD11c+/CD11b+ Spleen Cells and Impacts Disease Expression in Murine Lupus

Cunningham, Melissa A.; Wirth, Jena R.; Scott, Jennifer; Eudaly, Jackie; Collins, Erin; Gilkeson, Gary S.

doi:10.3389/fimmu.2016.00031

Cited by 22 publications

(22 citation statements)

References 44 publications

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“…nephritis in the TLR-stimulated group (glomerular score = 5, vs. 1, p < 0.0001) ( Figures 3D,E), but again not to the extent that we typically see in NZM2410 mice with end stage nephritis/nephrosis (terminal glomerular scores usually >14) (18,19). Death from a non-nephritis cause is further indicated by NZM2410 mice that died early (4-6 weeks post-treatment vs. 8 weeks).…”

Section: Tlr7 Stimulation Accelerates Glomerulonephritis In Nzm2410 Micementioning

confidence: 79%

TLR7 Agonism Accelerates Disease and Causes a Fatal Myeloproliferative Disorder in NZM 2410 Lupus Mice

et al. 2020

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Murine models of lupus, both spontaneous and inducible, are valuable instruments to study SLE pathogenesis. Accelerants such as Type I IFN are often used to trigger earlier disease onset. We used a topical TLR7 agonist, previously reported to induce lupus-like disease in WT mice within weeks, to validate this data in C57BL/6j mice, and to test TLR7 agonism as an accelerant in lupus-prone NZM2410 mice. We found that TLR7-stimulated B6 and NZM2410 mice had significantly reduced survival and exhibited profound splenomegaly with significantly reduced B cells (4 vs. 40%), and T cells (8 vs. 31%). Spleen pathology and IHC revealed massive expansion of F4/80+ cells in TLR7-treated mice consistent with histiocytosis. While resiqimod treatment caused mild autoimmunity in B6 mice and accelerated autoimmunity in NZM2410 mice, it did not cause significant nephritis or proteinuria in either strain (renal function intact at death). Given the macrophage expansion, cytopenias, and disruption of normal splenic lymphoid follicle architecture, histiocytic sarcoma is favored as the cause of death. An alternative etiology is a macrophage activation syndrome (MAS)-like syndrome, since the mice also had a transaminitis and histologic hemophagocytosis in the setting of their rapid mortality. For investigators who are focused on murine models of lupus nephritis, this model is not ideal when utilizing B6 mice, however topical resiqimod may prove useful to accelerate autoimmunity and nephritis in NZM2410 mice, or potentially to investigate secondary complications of lupus such as histiocytic diseases or macrophage activation like syndromes.

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Section: Tlr7 Stimulation Accelerates Glomerulonephritis In Nzm2410 Micementioning

confidence: 79%

TLR7 Agonism Accelerates Disease and Causes a Fatal Myeloproliferative Disorder in NZM 2410 Lupus Mice

et al. 2020

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“…Infiltration of macrophages, PMNs, DCs, T‐ and B‐lymphocytes to the spleen and their activation orchestrates innate and adaptive responses involved in lupus pathogenesis . Thus, we determined the impact of IRAK4 kinase activity on leukocyte infiltration to the spleen and their activation statuses in F2 BXSB/ Yaa x C57BL/6J mice expressing KI or WT IRAK4 compared with these parameters in control mice.…”

Section: Resultsmentioning

confidence: 99%

“…Migration of macrophages and DCs to the spleen regulates innate immunity and promotes activation of B‐ and T‐lymphocytes . Since lupus is associated with increased infiltration of the spleen with macrophages, PMNs, DCs, T‐ and B‐lymphocytes, and their increased activation , we studied whether expression of kinase‐inactive IRAK4 in lupus‐prone mice affects these parameters. BXSB/ Yaa mice expressing kinase‐sufficient IRAK4 developed exaggerated lupus and exhibited higher numbers of F4/80 + splenic macrophages that were activated, judged by their higher levels of TNF‐α, compared with BXSB/ Yaa mice harboring kinase‐inactive IRAK4.…”

Section: Discussionmentioning

confidence: 99%

Deficiency in IRAK4 activity attenuates manifestations of murine Lupus

et al. 2017

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Interleukin-1 receptor-associated kinase (IRAK) 4 mediates host defense against infections. As an active kinase, IRAK4 elicits full spectra of myeloid differentiation primary response protein (MyD) 88-dependent responses, while kinase-inactive IRAK4 induces a subset of cytokines and negative regulators whose expression is not regulated by mRNA stability. IRAK4 kinase activity is critical for resistance against Streptococcus pneumonia, but its involvement in autoimmunity is incompletely understood. In this study, we determined the role of IRAK4 kinase activity in murine lupus. Lupus development in BXSB mice expressing the Y chromosome autoimmunity accelerator (Yaa) increased basal and Toll-like receptor (TLR) 4/7-induced phosphorylation of mitogen-activated protein kinases, p65 nuclear factor-κB (NF-κB), enhanced tumor necrosis factor (TNF)-α and C-C motif chemokine ligand (CCL) 5 gene expression in splenic macrophages, but decreased levels of Toll-interacting protein and IRAK-M, without affecting IRAK4 or IRAK1 expression. Mice harboring kinase-inactive IRAK4 on the lupus-prone Yaa background manifested blunted TLR signaling in macrophages and reduced glomerulonephritis, splenomegaly, serum anti-nuclear antibodies, numbers of splenic macrophages, total and TNF-α+ dendritic cells, activated T- and B-lymphocytes, and lower TNF-α expression in macrophages compared to lupus-prone mice with functional IRAK4. Thus, IRAK4 kinase activity contributes to murine lupus and could represent a new therapeutic target.

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“…Ovariectomy was performed in DCM female mice at 4 weeks of age prior to sexual maturation [ 35 ]. Mice were kept under 1–2%isoflurane anesthesia during surgical procedure.…”

Section: Methodsmentioning

confidence: 99%

Enhanced heart failure, mortality and renin activation in female mice with experimental dilated cardiomyopathy

et al. 2017

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Dilated cardiomyopathy (DCM) is the major cause of heart failure affecting both women and men. Limited clinical studies show conflicting data in sex-related differences in the progression of dilated cardiomyopathy and heart failure (HF) outcomes. We examined the comparative sex-related progression of cardiomyopathy and the development of HF (at 4, 7, 13 weeks of age) in a well-established, transgenic mouse model of DCM that recapitulates the progressive stages of human HF. By 13 weeks of age, female mice with DCM had more severe left ventricular systolic dysfunction, left ventricular dilation and wall thinning (P<0.001 for all) than age-matched male mice with DCM. Female mice also had greater lung edema (P<0.001), cardiac fibrosis (P<0.01) and pleural effusions, which were not rescued by ovariectomy. By comparison to DCM male mice at 13 weeks, these pathological changes in female mice with DCM, were associated with significant increases in plasma active renin (P<0.01), angiotensin II (P<0.01) and aldosterone levels (P<0.001). In comparison to DCM male mice, DCM female mice also showed differential expression of the natriuretic peptide system with lower corin and higher ANP, BNP and cGMP levels at 13 weeks of age. We conclude, that female mice with experimental DCM have an accelerated progression of cardiomyopathy and HF, which was not corrected by early ovariectomy. These alterations are associated with early renin activation with increased angiotensin II and aldosterone levels, and altered expression of the natriuretic peptide system.

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Early Ovariectomy Results in Reduced Numbers of CD11c+/CD11b+ Spleen Cells and Impacts Disease Expression in Murine Lupus

Cited by 22 publications

References 44 publications

TLR7 Agonism Accelerates Disease and Causes a Fatal Myeloproliferative Disorder in NZM 2410 Lupus Mice

TLR7 Agonism Accelerates Disease and Causes a Fatal Myeloproliferative Disorder in NZM 2410 Lupus Mice

Deficiency in IRAK4 activity attenuates manifestations of murine Lupus

Enhanced heart failure, mortality and renin activation in female mice with experimental dilated cardiomyopathy

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