Neutrophil Gelatinase–Associated Lipocalin Protects from ANCA-Induced GN by Inhibiting TH17 Immunity

Schreiber, Adrian; Rousselle, Anthony; Klocke, Jan; Bachmann, S.; Popović, Sunčica; Bontscho, Julia; Schmidt‐Ott, Kai M.; Siffrin, Volker; Jerke, Uwe; Ashraf, Muhammad; Panzer, Ulf; Kettritz, Ralph

doi:10.1681/asn.2019090879

Cited by 23 publications

(22 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Now, we show that increased CSF2 augmented the capacity of ANCA-stimulated monocytes to release IL-1β and subsequently to induce T H 17 polarisation in vitro. T H 17 cells play an important role in the pathogenesis of NCGN,32 including NCGN induced by ANCA 33. Conceivably, additional monocyte-mediated disease mechanisms are at work.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

CSF2-dependent monocyte education in the pathogenesis of ANCA-induced glomerulonephritis

et al. 2022

Self Cite

View full text Add to dashboard Cite

ObjectivesMyeloid cell activation by antineutrophil cytoplasmic antibody (ANCA) is pivotal for necrotising vasculitis, including necrotising crescentic glomerulonephritis (NCGN). In contrast to neutrophils, the contribution of classical monocyte (CM) and non-classical monocyte (NCM) remains poorly defined. We tested the hypothesis that CMs contribute to antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and that colony-stimulating factor-2 (CSF2, granulocyte-macrophage colony-stimulating factor (GM-CSF)) is an important monocyte-directed disease modifier.MethodsMyeloperoxidase (MPO)-immunised MPO−/− mice were transplanted with haematopoietic cells from wild-type (WT) mice, C–C chemokine receptor 2 (CCR2)−/− mice to abrogate CM, or transcription factor CCAAT–enhancer-binding protein beta (C/EBPβ)−/− mice to reduce NCM, respectively. Monocytes were stimulated with CSF2, and CSF2 receptor subunit beta (CSF2rb)-deficient mice were used. Urinary monocytes and CSF2 were quantified and kidney Csf2 expression was analysed. CSF2-blocking antibody was used in the nephrotoxic nephritis (NTN) model.ResultsCompared with WT mice, CCR2−/− chimeric mice showed reduced circulating CM and were protected from NCGN. C/EBPβ−/− chimeric mice lacked NCM but developed NCGN similar to WT chimeric mice. Kidney and urinary CSF2 were upregulated in AAV mice. CSF2 increased the ability of ANCA-stimulated monocytes to generate interleukin-1β and to promote TH17 effector cell polarisation. CSF2rb−/− chimeric mice harboured reduced numbers of kidney TH17 cells and were protected from NCGN. CSF2 neutralisation reduced renal damage in the NTN model. Finally, patients with active AAV displayed increased urinary CM numbers, CSF2 levels and expression of GM-CSF in infiltrating renal cells.ConclusionsCMs but not NCMs are important for inducing kidney damage in AAV. CSF2 is a crucial pathological factor by modulating monocyte proinflammatory functions and thereby TH17 cell polarisation.

show abstract

Section: Discussionmentioning

confidence: 99%

“…T H 17 cells play an important role in the pathogenesis of NCGN, 32 including NCGN induced by ANCA. 33 Conceivably, additional monocyte-mediated disease mechanisms are at work. For example, monocytes release extracellular traps in response to ANCA that can directly induce endothelial cell damage (personal data).…”

Section: Discussionmentioning

confidence: 99%

CSF2-dependent monocyte education in the pathogenesis of ANCA-induced glomerulonephritis

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Iron import into T cells seems also to affect T cell polarization, as import of iron via iron-siderophore-laden LCN2 has been demonstrated to suppress TH17 polarization in a vasculitis model ( 262 ).…”

Section: Immune Cells Under Iron-deficient Conditionsmentioning

confidence: 99%

Iron-Deficiency in Atopic Diseases: Innate Immune Priming by Allergens and Siderophores

Roth‐Walter

2022

Front. Allergy

View full text Add to dashboard Cite

Although iron is one of the most abundant elements on earth, about a third of the world's population are affected by iron deficiency. Main drivers of iron deficiency are beside the chronic lack of dietary iron, a hampered uptake machinery as a result of immune activation. Macrophages are the principal cells distributing iron in the human body with their iron restriction skewing these cells to a more pro-inflammatory state. Consequently, iron deficiency has a pronounced impact on immune cells, favoring Th2-cell survival, immunoglobulin class switching and primes mast cells for degranulation. Iron deficiency during pregnancy increases the risk of atopic diseases in children, while both children and adults with allergy are more likely to have anemia. In contrast, an improved iron status seems to protect against allergy development. Here, the most important interconnections between iron metabolism and allergies, the effect of iron deprivation on distinct immune cell types, as well as the pathophysiology in atopic diseases are summarized. Although the main focus will be humans, we also compare them with innate defense and iron sequestration strategies of microbes, given, particularly, attention to catechol-siderophores. Similarly, the defense and nutritional strategies in plants with their inducible systemic acquired resistance by salicylic acid, which further leads to synthesis of flavonoids as well as pathogenesis-related proteins, will be elaborated as both are very important for understanding the etiology of allergic diseases. Many allergens, such as lipocalins and the pathogenesis-related proteins, are able to bind iron and either deprive or supply iron to immune cells. Thus, a locally induced iron deficiency will result in immune activation and allergic sensitization. However, the same proteins such as the whey protein beta-lactoglobulin can also transport this precious micronutrient to the host immune cells (holoBLG) and hinder their activation, promoting tolerance and protecting against allergy. Since 2019, several clinical trials have also been conducted in allergic subjects using holoBLG as a food for special medical purposes, leading to a reduction in the allergic symptom burden. Supplementation with nutrient-carrying lipocalin proteins can circumvent the mucosal block and nourish selectively immune cells, therefore representing a new dietary and causative approach to compensate for functional iron deficiency in allergy sufferers.

show abstract

“…108 Changes in circulating T-cell subsets and cytokines have been described in patients with podocytopathies. 109,110 Compared with the healthy control group, the number of regulatory T cells (T cells that inhibit the immune response) in patients with podocytopathies also decreased and tended to be normal when proteinuria was relieved. 111,112 In patients with primary podocytopathies, the role of circulating permeability factors, such as cardiotrophin-like cytokine 1, soluble urokinase plasma activator receptor (suPAR), and anti-CD40 IgG, has also been gradually confirmed.…”

Section: Immunological Factorsmentioning

confidence: 99%

“…The effectiveness of glucocorticoids and immunosuppressive agents in many podocyte diseases without a genetic background indicates that the immune system plays a central role in the pathogenesis of these diseases 108 . Changes in circulating T‐cell subsets and cytokines have been described in patients with podocytopathies 109,110 . Compared with the healthy control group, the number of regulatory T cells (T cells that inhibit the immune response) in patients with podocytopathies also decreased and tended to be normal when proteinuria was relieved 111,112 .…”

Section: Pathogenesis Of Podocytopathiesmentioning

confidence: 99%

A critical role of the podocyte cytoskeleton in the pathogenesis of glomerular proteinuria and autoimmune podocytopathies

Lan

Liu

et al. 2022

Acta Physiologica

View full text Add to dashboard Cite

Selective glomerular filtration relies on the membrane separating the glomerular arterioles from the Bowman space. As a major component of the glomerular filtration barrier, podocytes form foot processes by the actin cytoskeleton, which dynamically adjusts in response to environmental changes to maintain filtration barrier integrity. The slit diaphragms bridge the filtration slits between neighboring foot processes and act as signaling hubs interacting with the actin cytoskeleton. Focal adhesions relay signals to regulate actin dynamics while allowing podocyte adherence to the basement membrane. Mutations in actin regulatory and signaling proteins may disrupt the actin cytoskeleton, resulting in foot process retraction, effacement, and proteinuria. Large‐scale gene expression profiling platforms, transgenic animal models, and other in vivo gene delivery methods now enhance our understanding of the interactions among podocyte focal adhesions, slit diaphragms, and actin dynamics. In addition, our team found that at least 66% of idiopathic nephrotic syndrome (INS) children have podocyte autoantibodies, which was defined as a new disease subgroup‐, autoimmune podocytopathies. This review outlines the pathophysiological mechanisms of podocyte cytoskeleton protein interactions in proteinuria and glomerular podocytopathy.

show abstract

Neutrophil Gelatinase–Associated Lipocalin Protects from ANCA-Induced GN by Inhibiting TH17 Immunity

Cited by 23 publications

References 37 publications

CSF2-dependent monocyte education in the pathogenesis of ANCA-induced glomerulonephritis

CSF2-dependent monocyte education in the pathogenesis of ANCA-induced glomerulonephritis

Iron-Deficiency in Atopic Diseases: Innate Immune Priming by Allergens and Siderophores

A critical role of the podocyte cytoskeleton in the pathogenesis of glomerular proteinuria and autoimmune podocytopathies

Contact Info

Product

Resources

About