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Article ; Online: Mesangial Cells in Lupus Nephritis.

Nowling, Tamara K

2022 Volume 23, Issue 12, Page(s) 83

Abstract: Purpose of review: Mesangial cells are critical for the proper function of the glomerulus, playing roles in structural support and injury repair. However, they are also early responders to glomerular immune complex deposition and contribute to ... ...

Abstract	Purpose of review: Mesangial cells are critical for the proper function of the glomerulus, playing roles in structural support and injury repair. However, they are also early responders to glomerular immune complex deposition and contribute to inflammation and fibrosis in lupus nephritis. This review highlights recent studies identifying signaling pathways and mediators in mesangial cell response to lupus-relevant stimuli. Recent findings: Anti-dsDNA antibodies, serum, or plasma from individuals with lupus nephritis, or specific pathologic factors activated multiple signaling pathways. These pathways largely included JAK/STAT/SOCS, PI3K/AKT, and MAPK and led to induction of proliferation and expression of multiple proinflammatory cytokines, growth factors, and profibrotic factors. NFκB activation was a common mediator of response. Mesangial cells proliferate and express a wide array of proinflammatory/profibrotic factors in response to a variety of lupus-relevant pathologic stimuli. While some of the responses are similar, the mechanisms involved appear to be diverse depending on the stimulus. Future studies are needed to fully elucidate these mechanisms with respect to the diverse milieu of stimuli.
MeSH term(s)	Antibodies, Antinuclear ; Fibrosis ; Humans ; Lupus Nephritis/pathology ; Mesangial Cells/pathology ; Phosphatidylinositol 3-Kinases
Chemical Substances	Antibodies, Antinuclear ; anti-dsDNA autoantibody
Language	English
Publishing date	2022-01-05
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2057357-1
ISSN	1534-6307 ; 1523-3774
ISSN (online)	1534-6307
ISSN	1523-3774
DOI	10.1007/s11926-021-01048-0
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Article ; Online: Role of the transcription factor Fli-1 on the CXCL10/CXCR3 Axis.

Wang, Xuan / Richard, Mara Lennard / Caldwell, Tomika S / Sundararaj, Kamala / Sato, Shuzo / Nowling, Tamara K / Zhang, Xian K

Frontiers in immunology

2023 Volume 14, Page(s) 1219279

Abstract: The transcription factor Fli-1, a member of the ETS family of transcription factors, is implicated in the pathogenesis of lupus disease. Reduced Fli-1 expression in lupus mice leads to decreased ... ...

Abstract	The transcription factor Fli-1, a member of the ETS family of transcription factors, is implicated in the pathogenesis of lupus disease. Reduced Fli-1 expression in lupus mice leads to decreased renal
MeSH term(s)	Animals ; Humans ; Mice ; Chemokine CXCL10/genetics ; Chemokine CXCL10/metabolism ; Endothelial Cells/metabolism ; Kidney/pathology ; Mice, Inbred MRL lpr ; Proto-Oncogene Protein c-fli-1/genetics ; Proto-Oncogene Protein c-fli-1/metabolism ; Receptors, CXCR3/genetics ; Receptors, CXCR3/metabolism
Chemical Substances	Chemokine CXCL10 ; CXCL10 protein, human ; CXCR3 protein, human ; Proto-Oncogene Protein c-fli-1 ; Receptors, CXCR3 ; FLI1 protein, human ; Fli1 protein, mouse
Language	English
Publishing date	2023-09-15
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1219279
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Article: Glycosphingolipid Levels in Urine Extracellular Vesicles Enhance Prediction of Therapeutic Response in Lupus Nephritis.

Troyer, Brian / Rodgers, Jessalyn / Wolf, Bethany J / Oates, James C / Drake, Richard R / Nowling, Tamara K

Metabolites

2022 Volume 12, Issue 2

Abstract: The development of nephritis increases the risk of morbidity and mortality in systemic lupus erythematosus (SLE) patients. While standard induction therapies, such as mycophenolate mofetil (MMF) induce clinical remission (i.e., complete response) in ... ...

Abstract	The development of nephritis increases the risk of morbidity and mortality in systemic lupus erythematosus (SLE) patients. While standard induction therapies, such as mycophenolate mofetil (MMF) induce clinical remission (i.e., complete response) in approximately 50% of SLE patients with nephritis, many patients fail to respond. Therapeutic response is often not assessed until 6-12 months after beginning treatment. Those patients that fail to respond to treatment continue to accumulate organ damage, thus, there is a critical need to predict which patients will fail therapy before beginning treatment, allowing physicians to optimize therapy. Our previous studies demonstrated elevated urine, but not serum, glycosphingolipids (GSLs) in SLE patients with nephritis compared to SLE patients without nephritis, suggesting the urine GSLs were derived from the kidney. In this study, we measured the GSLs hexosylceramide and lactosylceramide in extracellular vesicles isolated from longitudinal urine samples of LN patients that were treated with MMF for 12 months. GSL levels were significantly elevated in the baseline samples (prior to treatment) of non-responders compared to complete responders. While a few other proteins measured in the whole urine were higher in non-responders at baseline, only GSLs demonstrated a significant ability to discriminate treatment response in lupus nephritis patients.
Language	English
Publishing date	2022-02-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662251-8
ISSN	2218-1989
ISSN	2218-1989
DOI	10.3390/metabo12020134
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Article ; Online: The role of neuraminidase 1 (NEU1) in cytokine release by primary mouse mesangial cells and disease outcomes in murine lupus nephritis.

Rodgers, Jessalyn / Sundararaj, Kamala / Bruner, Evelyn / Wolf, Bethany / Nowling, Tamara K

Autoimmunity

2021 Volume 54, Issue 3, Page(s) 163–175

Abstract: The importance of altered glycosphingolipid (GSL) metabolism is increasingly gaining attention as a characteristic of multiple chronic kidney diseases. Previously, we reported elevated levels of GSLs and neuraminidase (NEU) enzyme activity/expression in ... ...

Abstract	The importance of altered glycosphingolipid (GSL) metabolism is increasingly gaining attention as a characteristic of multiple chronic kidney diseases. Previously, we reported elevated levels of GSLs and neuraminidase (NEU) enzyme activity/expression in the urine or kidney of lupus patients and lupus-prone mice, and demonstrated NEU activity mediates the production of cytokines by lupus-prone mouse primary mesangial cells. This mediation occurs in part through TLR4 and p38/ERK MAPK signalling in response to lipopolysaccharide (LPS) and lupus serum (LS). However, the precise role of NEU1, the most abundant NEU in the kidney, is incompletely known. In this study, we investigated the effect of genetically reduced
MeSH term(s)	Animals ; Cytokines/metabolism ; Disease Models, Animal ; Female ; Kidney/drug effects ; Kidney/metabolism ; Lipopolysaccharides/pharmacology ; Lupus Nephritis/metabolism ; MAP Kinase Signaling System/drug effects ; Mesangial Cells/drug effects ; Mesangial Cells/metabolism ; Mice ; Mice, Inbred C57BL ; Neuraminidase/metabolism
Chemical Substances	Cytokines ; Lipopolysaccharides ; Neu1 protein, mouse (EC 3.2.1.18) ; Neuraminidase (EC 3.2.1.18)
Language	English
Publishing date	2021-03-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1025450-x
ISSN	1607-842X ; 0891-6934
ISSN (online)	1607-842X
ISSN	0891-6934
DOI	10.1080/08916934.2021.1897978
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Article ; Online: The role of neuraminidase in TLR4-MAPK signalling and the release of cytokines by lupus serum-stimulated mesangial cells.

Sundararaj, Kamala / Rodgers, Jessalyn / Angel, Peggi / Wolf, Bethany / Nowling, Tamara K

Immunology

2021 Volume 162, Issue 4, Page(s) 418–433

Abstract: Previously, we demonstrated neuraminidase (NEU) activity or NEU1 expression, specifically, is increased in the kidneys of lupus mice and urine of human patients with nephritis. Additionally, NEU activity mediates IL-6 secretion from lupus-prone MRL/lpr ... ...

Abstract	Previously, we demonstrated neuraminidase (NEU) activity or NEU1 expression, specifically, is increased in the kidneys of lupus mice and urine of human patients with nephritis. Additionally, NEU activity mediates IL-6 secretion from lupus-prone MRL/lpr primary mouse mesangial cells (MCs) in response to an IgG mimic. IL-6 mediates glomerular inflammation and promotes tissue damage in patients and mouse strains with lupus nephritis. This study further elucidates the mechanisms by which NEU activity and NEU1 specifically mediates the release of IL-6 and other cytokines from lupus-prone MCs. We demonstrate significantly increased release of multiple cytokines and NEU activity in MRL/lpr MCs in response to serum from MRL/lpr mice (lupus serum). Inhibiting NEU activity significantly reduced secretion of three of those cytokines: IL-6, GM-CSF and MIP1α. Message levels of Il-6 and Gm-csf were also increased in response to lupus serum and reduced when NEU activity was inhibited. Neutralizing antibodies to cell-surface receptors and MAPK inhibitors in lupus serum- or LPS-stimulated MCs indicate TLR4 and p38 or ERK MAP kinase signalling play key roles in the NEU-mediated secretion of IL-6. Significantly reduced IL-6 release was observed in C57BL/6 (B6) Neu1+/+ primary MCs compared with wild-type (Neu1+/+) B6 MCs in response to lupus serum. Additional results show inhibiting NEU activity significantly increases sialic acid-containing N-glycan levels. Together, our novel observations support a role for NEU activity, and specifically NEU1, in mediating release of IL-6 from lupus-prone MCs in response to lupus serum through a TLR4-p38/ERK MAPK signalling pathway that likely includes desialylation of glycoproteins.
MeSH term(s)	Animals ; Cells, Cultured ; Cytokines/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Female ; Gene Expression Regulation ; Humans ; Kidney/metabolism ; Kidney/pathology ; Lupus Erythematosus, Systemic/metabolism ; Lupus Nephritis/metabolism ; Male ; Mesangial Cells/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Inbred MRL lpr ; Neuraminidase/genetics ; Neuraminidase/metabolism ; Serum/metabolism ; Signal Transduction ; Toll-Like Receptor 4/metabolism
Chemical Substances	Cytokines ; Toll-Like Receptor 4 ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; Neu1 protein, mouse (EC 3.2.1.18) ; Neuraminidase (EC 3.2.1.18)
Language	English
Publishing date	2021-01-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/imm.13294
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Article: Formal neurocognitive function and anti-N-methyl-D-aspartate receptor antibodies in paediatric lupus.

Nowling, Tamara K / Kral, Mary / Wolf, Bethany / Gilkeson, Gary / Ruth, Natasha McKerran

Lupus science & medicine

2021 Volume 8, Issue 1

Abstract: Objective: SLE is a chronic multisystem autoimmune inflammatory disease impacting a number of organs, including the central nervous system (CNS). The pathophysiology of CNS lupus is multifactorial, making diagnosis problematic. Neurocognitive (NC) ... ...

Abstract	Objective: SLE is a chronic multisystem autoimmune inflammatory disease impacting a number of organs, including the central nervous system (CNS). The pathophysiology of CNS lupus is multifactorial, making diagnosis problematic. Neurocognitive (NC) testing and specific biomarkers to identify the development of neuropsychiatric (NP) symptoms in lupus are needed. Paediatric patients with SLE have high incidence of NP disease . While serum anti-N-methyl-D-aspartate receptor (NMDAR) antibodies have shown promise as a biomarker of NP in adults with SLE, much less is known with regard to paediatric patients with SLE. Methods: We performed a cross-sectional study in paediatric patients with SLE. Serum NMDAR antibodies were measured and compared with levels in patients with juvenile idiopathic arthritis (JIA). Formal NC testing was performed in accordance with the Childhood Arthritis & Rheumatology Research Alliance neuropsychological core test battery. NC functioning was compared in the two groups and with NMDAR antibody levels. Results: Serum NMDAR antibody levels were significantly higher in paediatric patients with SLE compared with patients with JIA. There were no significant correlations between NMDAR antibody levels and any measure of NC functioning. In an exploratory examination of anti-ribosomal P (RibP) antibody and NC functioning in a subset of patients with SLE, RibP antibody-positive patients exhibited worse scores for Verbal Memory Index and Design Fluency Test Switching compared with RibP antibody-negative patients. A globally significant association between disease status and NC functioning was observed. Specifically, patients with SLE had lower scores compared with patients with JIA for full-scale IQ, letter-word recognition, reading fluency and calculation skills after adjusting for multiple comparisons. Conclusion: These collective results suggest that although serum NMDAR may serve as a biomarker, formal NC testing is superior in identifying paediatric patients with SLE with NP manifestations. RibP also may potentially serve as a biomarker of NP manifestations in paediatric patients with SLE. Additional and longitudinal studies are needed.
MeSH term(s)	Adolescent ; Antibodies, Antinuclear ; Autoantibodies ; Child ; Cross-Sectional Studies ; Female ; Humans ; Lupus Vasculitis, Central Nervous System ; Male ; Receptors, N-Methyl-D-Aspartate
Chemical Substances	Antibodies, Antinuclear ; Autoantibodies ; Receptors, N-Methyl-D-Aspartate
Language	English
Publishing date	2021-03-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2779620-6
ISSN	2053-8790
ISSN	2053-8790
DOI	10.1136/lupus-2020-000462
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Article ; Online: Metabolic Markers and Association of Biological Sex in Lupus Nephritis.

Wolf, Bethany / Blaschke, Calvin R K / Mungaray, Sandy / Weselman, Bryan T / Stefanenko, Mariia / Fedoriuk, Mykhailo / Bai, Hongxia / Rodgers, Jessalyn / Palygin, Oleg / Drake, Richard R / Nowling, Tamara K

International journal of molecular sciences

2023 Volume 24, Issue 22

Abstract: Lupus nephritis (LN) is a serious complication for many patients who develop systemic lupus erythematosus, which primarily afflicts women. Our studies to identify biomarkers and the pathogenic mechanisms underlying LN will provide a better understanding ... ...

Abstract	Lupus nephritis (LN) is a serious complication for many patients who develop systemic lupus erythematosus, which primarily afflicts women. Our studies to identify biomarkers and the pathogenic mechanisms underlying LN will provide a better understanding of disease progression and sex bias, and lead to identification of additional potential therapeutic targets. The glycosphingolipid lactosylceramide (LacCer) and N-linked glycosylated proteins (N-glycans) were measured in urine and serum collected from LN and healthy control (HC) subjects (10 females and 10 males in each group). The sera from the LN and HC subjects were used to stimulate cytokine secretion and intracellular Ca
MeSH term(s)	Humans ; Female ; Male ; Lupus Nephritis/pathology ; Lupus Erythematosus, Systemic ; Biomarkers ; Cytokines ; Glycosphingolipids ; Polysaccharides
Chemical Substances	Biomarkers ; Cytokines ; Glycosphingolipids ; Polysaccharides
Language	English
Publishing date	2023-11-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms242216490
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Article ; Online: Targeting glycosphingolipid metabolism as a potential therapeutic approach for treating disease in female MRL/lpr lupus mice.

Nowling, Tamara K / Rodgers, Jessalyn / Thiyagarajan, Thirumagal / Wolf, Bethany / Bruner, Evelyn / Sundararaj, Kamala / Molano, Ivan / Gilkeson, Gary

PloS one

2020 Volume 15, Issue 3, Page(s) e0230499

Abstract: Glycosphingolipids (GSLs) hexosylceramides and lactosylceramides are elevated in lupus mice and human patients with nephritis. Whereas other renal diseases characterized by increased GSL levels are thought to be a result of upregulated GSL synthesis, our ...

Abstract	Glycosphingolipids (GSLs) hexosylceramides and lactosylceramides are elevated in lupus mice and human patients with nephritis. Whereas other renal diseases characterized by increased GSL levels are thought to be a result of upregulated GSL synthesis, our results suggest elevated hexosylceramides and lactosylceramides in lupus nephritis is a result of increased catabolism of ganglioside GM3 due to significantly increased neuraminidase (NEU) activity. Thus, we hypothesized GM3 would be decreased in lupus nephritis kidneys and blocking NEU activity would reduce GSLs and improve disease in lupus mice. Female MRL/lpr lupus mice were treated with water or the NEU inhibitor oseltamivir phosphate at the onset of proteinuria to block GSL catabolism. Age-matched (non-nephritic) female MRL/MpJ lupus mice served as controls. Renal GM3 levels were significantly higher in the nephritic MRL/lpr water-treated mice compared to non-nephritic MRL/MpJ mice, despite significantly increased renal NEU activity. Blocking GSL catabolism increased, rather than decreased, renal and urine GSL levels and disease was not significantly impacted. A pilot study treating MRL/lpr females with GlcCer synthase inhibitor Genz-667161 to block GSL synthesis resulted in a strong significant negative correlation between Genz-667161 dose and renal GSL hexosylceramide and GM3 levels. Splenomegaly was negatively correlated and serum IgG levels were marginally correlated with increasing Genz-667161 dose. These results suggest accumulation of renal GM3 may be due to dysregulation of one or more of the GSL ganglioside pathways and inhibiting GSL synthesis, but not catabolism, may be a therapeutic approach for treating lupus nephritis.
MeSH term(s)	Animals ; Ceramides/metabolism ; Female ; G(M3) Ganglioside/metabolism ; Glycosphingolipids/metabolism ; Kidney/drug effects ; Kidney/metabolism ; Lactosylceramides/metabolism ; Lupus Nephritis/drug therapy ; Lupus Nephritis/metabolism ; Mice ; Mice, Inbred MRL lpr ; Neuraminidase/metabolism ; Oseltamivir/analogs & derivatives ; Oseltamivir/therapeutic use ; Phosphorous Acids/therapeutic use ; Pilot Projects ; Proteinuria/drug therapy ; Proteinuria/metabolism
Chemical Substances	Ceramides ; G(M3) Ganglioside ; Glycosphingolipids ; Lactosylceramides ; Phosphorous Acids ; tamiphosphor ; Oseltamivir (20O93L6F9H) ; Neuraminidase (EC 3.2.1.18)
Language	English
Publishing date	2020-03-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0230499
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Article ; Online: Mechanisms of tissue injury in lupus nephritis.

Nowling, Tamara K / Gilkeson, Gary S

Arthritis research & therapy

2011 Volume 13, Issue 6, Page(s) 250

Abstract: Systemic lupus erythematosus is a prototypic autoimmune disease characterized by autoantibody production and immune complex formation/deposition in target organs such as the kidney. Resultant local inflammation then leads to organ damage. Nephritis, a ... ...

Abstract	Systemic lupus erythematosus is a prototypic autoimmune disease characterized by autoantibody production and immune complex formation/deposition in target organs such as the kidney. Resultant local inflammation then leads to organ damage. Nephritis, a major cause of morbidity and mortality in patients with lupus, occurs in approximately 50% of lupus patients. In the present review, we provide an overview of the current research and knowledge concerning mechanisms of renal injury in both lupus-prone mouse models and human lupus patients.
MeSH term(s)	Animals ; Autoantibodies/immunology ; Autoantibodies/metabolism ; Cytokines/immunology ; Cytokines/metabolism ; Disease Models, Animal ; Humans ; Kidney/immunology ; Kidney/metabolism ; Kidney/pathology ; Lupus Erythematosus, Systemic/complications ; Lupus Erythematosus, Systemic/immunology ; Lupus Erythematosus, Systemic/metabolism ; Lupus Nephritis/etiology ; Lupus Nephritis/immunology ; Lupus Nephritis/metabolism ; Mice
Chemical Substances	Autoantibodies ; Cytokines
Language	English
Publishing date	2011-12-21
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2107602-9
ISSN	1478-6362 ; 1478-6354
ISSN (online)	1478-6362
ISSN	1478-6354
DOI	10.1186/ar3528
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Article ; Online: Targeting glycosphingolipid metabolism as a potential therapeutic approach for treating disease in female MRL/lpr lupus mice.

Tamara K Nowling / Jessalyn Rodgers / Thirumagal Thiyagarajan / Bethany Wolf / Evelyn Bruner / Kamala Sundararaj / Ivan Molano / Gary Gilkeson

PLoS ONE, Vol 15, Iss 3, p e

2020 Volume 0230499

Abstract	Glycosphingolipids (GSLs) hexosylceramides and lactosylceramides are elevated in lupus mice and human patients with nephritis. Whereas other renal diseases characterized by increased GSL levels are thought to be a result of upregulated GSL synthesis, our results suggest elevated hexosylceramides and lactosylceramides in lupus nephritis is a result of increased catabolism of ganglioside GM3 due to significantly increased neuraminidase (NEU) activity. Thus, we hypothesized GM3 would be decreased in lupus nephritis kidneys and blocking NEU activity would reduce GSLs and improve disease in lupus mice. Female MRL/lpr lupus mice were treated with water or the NEU inhibitor oseltamivir phosphate at the onset of proteinuria to block GSL catabolism. Age-matched (non-nephritic) female MRL/MpJ lupus mice served as controls. Renal GM3 levels were significantly higher in the nephritic MRL/lpr water-treated mice compared to non-nephritic MRL/MpJ mice, despite significantly increased renal NEU activity. Blocking GSL catabolism increased, rather than decreased, renal and urine GSL levels and disease was not significantly impacted. A pilot study treating MRL/lpr females with GlcCer synthase inhibitor Genz-667161 to block GSL synthesis resulted in a strong significant negative correlation between Genz-667161 dose and renal GSL hexosylceramide and GM3 levels. Splenomegaly was negatively correlated and serum IgG levels were marginally correlated with increasing Genz-667161 dose. These results suggest accumulation of renal GM3 may be due to dysregulation of one or more of the GSL ganglioside pathways and inhibiting GSL synthesis, but not catabolism, may be a therapeutic approach for treating lupus nephritis.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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