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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Cell Dev. Biol. | doi: 10.3389/fcell.2019.00252

NLRP2 regulates proinflammatory and antiapoptotic responses in proximal tubular epithelial cells

 marianna n. rossi1, Antonia pascarella1, valerio licursi2, ivan caiello1, anna taranta1, laura r. rega1,  Elena Levtchenko3, francesco emma1, fabrizio De benedetti1 and  Giusi Prencipe1*
  • 1Bambino Gesù Children Hospital (IRCCS), Italy
  • 2Department of Biology and Biotechnology Charles Darwin, Faculty of Mathematical, Physical and Natural Sciences, Sapienza University of Rome, Italy
  • 3University Hospitals Leuven, Belgium

Nod-like Receptor Pyrin domain containing proteins (NLRPs) expressed by resident renal cells may contribute to the pathogenesis of multiple renal diseases. Cystinosis is a genetic disorder that affects kidney and particularly proximal tubular epithelial cells (PTEC). Here, we investigated the expression of NLRP family members in human control and cystinotic conditionally immortalized PTEC. Among all the NLRPs tested, we found that NLRP2 is highly expressed in cystinostic PTEC, but not in PTEC from healthy subjects. The NLRP2 overexpression was confirmed in primary PTEC and in kidney biopsies from cystinotic patients. In order to elucidate the role of NLRP2 in PTEC, we stably transfected control PTEC with an NLRP2-containing plasmid. We showed that NLRP2 markedly increases the production of several NF-kB regulated cytokines and chemokines. Accordingly, we demonstrated that NLRP2 interacts with IKKa and positively regulates the DNA-binding activity of p50 and p65 NF-kB, by modulating the p65 NF-kB phosphorylation status in Serine 536. Transcriptome analysis revealed that NLRP2 also upregulates the expression of profibrotic mediators and reduces that of several interferon-inducible genes. Finally, NLRP2 overexpression decreased the apoptotic cell rate. Consistently, silencing of NLRP2 by small-interfering RNA in cystinotic PTEC resulted in a significant decrease in cytokine and chemokine production as well as in an increase in the apoptosis rate. Altogether, our data reveals a previously unrecognized role for NLRP2 in regulating proinflammatory, profibrotic and antiapoptotic responses in PTEC, through NF-kB activation. Moreover, our findings unveil a novel potential mechanism involving NLRP2 overexpression in the pathogenesis of cystinosis.

Keywords: Cystinosis, NLRP2, Proximal tubular epithelial cells, NF-kB, chronic kidney diseases

Received: 01 Jul 2019; Accepted: 11 Oct 2019.

Copyright: © 2019 rossi, pascarella, licursi, caiello, taranta, rega, Levtchenko, emma, De benedetti and Prencipe. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Giusi Prencipe, Bambino Gesù Children Hospital (IRCCS), Rome, 00165, Lazio, Italy, giusi.prencipe@opbg.net