Interaction between galectin-3 and cystinosin uncovers a pathogenic role of inflammation in kidney involvement of cystinosis

Lobry, Tatiana; Miller, Russell; Névo, Nathalie; Rocca, Céline J.; Zhang, Jinzhong; Catz, Sergio D.; Moore, Fiona; Thomas, Lucie; Pouly, Daniel; Bailleux, Anne; Guerrera, Ida Chiara; Gübler, Marie-Claire; Cheung, Wai W.; Mak, Robert H.; Montier, Tristan; Antignac, Corinne; Cherqui, Stéphanie

doi:10.1016/j.kint.2019.01.029

Cited by 28 publications

(26 citation statements)

References 51 publications

(64 reference statements)

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“…In addition, HSPCs isolated from the Rac2 −/− mouse model were enriched for a M(LPS/IFNγ) macrophage population but appeared to be as efficient in rescuing cystine build-up in the Ctns −/− mice as WT HSPCs. Our findings correlate with a recent study that demonstrated increased recruitment of proinflammatory immune cells in cystinosis, further highlighting the crucial role that inflammation plays in this disorder 49 . In addition, the dissonance between our in vitro and in vivo results reflects mounting evidence that the in vitro paradigm of macrophage activity can be a potentially misleading oversimplification 25 .…”

Section: Discussionsupporting

confidence: 91%

Macrophage polarization impacts tunneling nanotube formation and intercellular organelle trafficking

Goodman

Naphade

Khan

et al. 2019

Sci Rep

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Tunneling nanotubes (TNTs) are cellular extensions enabling cytosol-to-cytosol intercellular interaction between numerous cell types including macrophages. Previous studies of hematopoietic stem and progenitor cell (HSPC) transplantation for the lysosomal storage disorder cystinosis have shown that HSPC-derived macrophages form TNTs to deliver cystinosin-bearing lysosomes to cystinotic cells, leading to tissue preservation. Here, we explored if macrophage polarization to either proinflammatory M1-like M(LPS/IFNγ) or anti-inflammatory M2-like M(IL-4/IL-10) affected TNT-like protrusion formation, intercellular transport and, ultimately, the efficacy of cystinosis prevention. We designed new automated image processing algorithms used to demonstrate that LPS/IFNγ polarization decreased bone marrow-derived macrophages (BMDMs) formation of protrusions, some of which displayed characteristics of TNTs, including cytoskeletal structure, 3D morphology and size. In contrast, co-culture of macrophages with cystinotic fibroblasts yielded more frequent and larger protrusions, as well as increased lysosomal and mitochondrial intercellular trafficking to the diseased fibroblasts. Unexpectedly, we observed normal protrusion formation and therapeutic efficacy following disruption of anti-inflammatory IL-4/IL-10 polarization in vivo by transplantation of HSPCs isolated from the Rac2−/− mouse model. Altogether, we developed unbiased image quantification systems that probe mechanistic aspects of TNT formation and function in vitro, while HSPC transplantation into cystinotic mice provides a complex in vivo disease model. While the differences between polarization cell culture and mouse models exemplify the oversimplicity of in vitro cytokine treatment, they simultaneously demonstrate the utility of our co-culture model which recapitulates the in vivo phenomenon of diseased cystinotic cells stimulating thicker TNT formation and intercellular trafficking from macrophages. Ultimately, we can use both approaches to expand the utility of TNT-like protrusions as a delivery system for regenerative medicine.

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Section: Discussionsupporting

confidence: 91%

Macrophage polarization impacts tunneling nanotube formation and intercellular organelle trafficking

Goodman

Naphade

Khan

et al. 2019

Sci Rep

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“…42 Lobry et al, demonstrated that cystinosin loss-of-function results in galectin-3 overexpression in cystinotic mice kidneys, inducing macrophage infiltration and kidney disease progression. 43 In light of our present data taken together with the clinical findings, we indicate that the V-ATPase B1 subunit plays an important role in acid-base homeostasis and is involved in the occurrence of a generalized proximal renal tubular defect that could functionally overlap with the one seen in cystinosis.…”

Section: Metabolic and Proteomic Profiling Link The Lysosomal V-atpassupporting

confidence: 59%

The lysosomal V-ATPase B1 subunit in renal proximal tubule is linked to nephropathic cystinosis

Jamalpoor

Eerde

Lilien

et al. 2020

Preprint

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BackgroundRecently, a 23-month-old girl presented with increased granulocyte cystine levels, metabolic acidosis and symptoms of renal Fanconi syndrome. Cystinosis was suspected and treatment with electrolytes and cysteamine, a cystine depleting agent, was started that appeared effective. However, genetic testing did not detect any variants in CTNS (the gene affected in cystinosis) but instead revealed pathogenic variants in ATP6V1B1. ATP6V1B1 encodes the B1 subunit of the vacuolar H+-ATPase (V-ATPase), that is linked to autosomal recessive distal renal tubular acidosis, a metabolic disorder with an inappropriately alkaline urine and deafness. Here, the unknown link between ATP6V1B1 gene deficiency and proximal tubulopathy as well as a possible link to cystinosis pathophysiology was investigated.MethodsWe used CRISPR/Cas9 technology to selectively knockout the ATP6V1B1 or CTNS gene in human renal proximal tubule cells and compare their proteomic and metabolomic profile with isogenic wild type proximal tubule cells.ResultsATP6V1B1 was expressed along the human distal but also the proximal segments of the nephron. Consistent with the clinical data, loss of ATP6V1B1 in renal proximal tubule cells resulted in increased cystine levels with autophagy activation. Further, omics profiling showed that both ATP6V1B1-/- and CTNS-/- cells are in metabolic acidosis with impaired autophagy and signs of proximal tubular epithelial dysfunction.ConclusionWe identified the lysosomal V-ATPase B1 subunit to play an important role in proximal tubule function, regulating cystine transport and autophagy in human renal proximal tubule cells through its interaction with cystinosin and mTOR-signaling.

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“…In this issue of Kidney International, the group of scientists led by Lobry et al 6 have discovered a new role for cystinosin function that adds to the understanding of why affected patients may have compromised kidney function as well. Using an established mouse model of the disease, the cystinosin knockout mouse (CTNS-/-), they demonstrated that in the normal mouse, cystinosin directed a protein galectin-3 to be degraded intralysosomally.…”

Section: See Basic Research On Page 350mentioning

confidence: 99%

“…The field eagerly awaits therapies directed at altering the many cellular processes that are disturbed, and now we can add one related to renal inflammation mediated by galectin-3 based on the work by Lobry and colleagues. 6 Additionally, we await innovative stem cell-based therapies that are now ongoing for a possible cure for nephropathic cystinosis. The future prospects for treating this disease have never been brighter, given the better understanding of the many cellular processes altered by a defective cystinosin.…”

Section: See Basic Research On Page 350mentioning

confidence: 99%

Oh cystinosin: let me count the ways!

Langman

2019

Kidney International

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Interaction between galectin-3 and cystinosin uncovers a pathogenic role of inflammation in kidney involvement of cystinosis

Abstract: Interaction between galectin-3 and cystinosin uncovers a pathogenic role of inflammation in kidney involvement of cystinosis see commentary on page 275

Cited by 28 publications

References 51 publications

Macrophage polarization impacts tunneling nanotube formation and intercellular organelle trafficking

Macrophage polarization impacts tunneling nanotube formation and intercellular organelle trafficking

The lysosomal V-ATPase B1 subunit in renal proximal tubule is linked to nephropathic cystinosis

Oh cystinosin: let me count the ways!

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