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The macrophage phenotype and inflammasome component NLRP3 contributes to nephrocalcinosis-related chronic kidney disease independent from IL-1-mediated tissue injury.
- Source :
-
Kidney international [Kidney Int] 2018 Mar; Vol. 93 (3), pp. 656-669. Date of Electronic Publication: 2017 Dec 12. - Publication Year :
- 2018
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Abstract
- Primary/secondary hyperoxalurias involve nephrocalcinosis-related chronic kidney disease (CKD) leading to end-stage kidney disease. Mechanistically, intrarenal calcium oxalate crystal deposition is thought to elicit inflammation, tubular injury and atrophy, involving the NLRP3 inflammasome. Here, we found that mice deficient in NLRP3 and ASC adaptor protein failed to develop nephrocalcinosis, compromising conclusions on nephrocalcinosis-related CKD. In contrast, hyperoxaluric wild-type mice developed profound nephrocalcinosis. NLRP3 inhibition using the β-hydroxybutyrate precursor 1,3-butanediol protected such mice from nephrocalcinosis-related CKD. Interestingly, the IL-1 inhibitor anakinra had no such effect, suggesting IL-1-independent functions of NLRP3. NLRP3 inhibition using 1,3-butanediol treatment induced a shift of infiltrating renal macrophages from pro-inflammatory (CD45 <superscript>+</superscript> F4/80 <superscript>+</superscript> CD11b <superscript>+</superscript> CX3CR1 <superscript>+</superscript> CD206 <superscript>-</superscript> ) and pro-fibrotic (CD45 <superscript>+</superscript> F4/80 <superscript>+</superscript> CD11b <superscript>+</superscript> CX3CR1 <superscript>+</superscript> CD206 <superscript>+</superscript> TGFβ <superscript>+</superscript> ) to an anti-inflammatory (CD45 <superscript>+</superscript> F4/80 <superscript>+</superscript> CD11b <superscript>+</superscript> CD206 <superscript>+</superscript> TGFβ <superscript>-</superscript> ) phenotype, and prevented renal fibrosis. Finally, in vitro studies with primary murine fibroblasts confirmed the non-redundant role of NLRP3 in the TGF-β signaling pathway for fibroblast activation and proliferation independent of the NLRP3 inflammasome complex formation. Thus, nephrocalcinosis-related CKD involves NLRP3 but not necessarily via intrarenal IL-1 release but rather via other biological functions including TGFR signaling and macrophage polarization. Hence, NLRP3 may be a promising therapeutic target in hyperoxaluria and nephrocalcinosis.<br /> (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Butylene Glycols pharmacology
CARD Signaling Adaptor Proteins genetics
CARD Signaling Adaptor Proteins metabolism
Cells, Cultured
Disease Models, Animal
Female
Fibroblasts immunology
Fibroblasts metabolism
Fibroblasts pathology
Hyperoxaluria drug therapy
Hyperoxaluria immunology
Hyperoxaluria pathology
Inflammasomes drug effects
Inflammasomes genetics
Inflammasomes immunology
Interleukin-1 immunology
Kidney immunology
Kidney pathology
Macrophages drug effects
Macrophages immunology
Macrophages pathology
Male
Mice, Inbred C57BL
Mice, Knockout
NLR Family, Pyrin Domain-Containing 3 Protein antagonists & inhibitors
NLR Family, Pyrin Domain-Containing 3 Protein genetics
NLR Family, Pyrin Domain-Containing 3 Protein immunology
Nephrocalcinosis immunology
Nephrocalcinosis pathology
Nephrocalcinosis prevention & control
Phenotype
Receptors, Transforming Growth Factor beta metabolism
Renal Insufficiency, Chronic immunology
Renal Insufficiency, Chronic pathology
Renal Insufficiency, Chronic prevention & control
Signal Transduction
Cell Plasticity drug effects
Hyperoxaluria metabolism
Inflammasomes metabolism
Interleukin-1 metabolism
Kidney metabolism
Macrophages metabolism
NLR Family, Pyrin Domain-Containing 3 Protein metabolism
Nephrocalcinosis metabolism
Renal Insufficiency, Chronic metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1523-1755
- Volume :
- 93
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Kidney international
- Publication Type :
- Academic Journal
- Accession number :
- 29241624
- Full Text :
- https://doi.org/10.1016/j.kint.2017.09.022