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Glomerulonephritis and autoimmune vasculitis are independent of P2RX7 but may depend on alternative inflammasome pathways.

Title: Glomerulonephritis and autoimmune vasculitis are independent of P2RX7 but may depend on alternative inflammasome pathways.
Authors: Prendecki, M
McAdoo, SP
Turner-Stokes, T
Garcia-Diaz, A
Orriss, I
Woollard, KJ
Behmoaras, J
Cook, HT
Unwin, R
Pusey, CD
Aitman, TJ
Tam, FWK
Item Type: Journal Article
Abstract: P2RX7, an ionotropic receptor for extracellular ATP, is expressed on immune cells, including macrophages, monocytes and dendritic cells and is up-regulated on non-immune cells following injury. P2RX7 plays a role in many biological processes, including production of pro-inflammatory cytokines such as IL-1β via the canonical inflammasome pathway. P2RX7 has been shown to be important in inflammation and fibrosis and may also play a role in autoimmunity. We have developed and phenotyped a novel P2RX7 knock-out (KO) inbred rat strain and taking advantage of the human-resembling unique histopathological features of rat models of glomerulonephritis, we induced three models of disease: nephrotoxic nephritis, experimental autoimmune glomerulonephritis, and experimental autoimmune vasculitis. We found that deletion of P2RX7 does not protect rats from models of experimental glomerulonephritis or the development of autoimmunity. Notably, treatment with A-438079, a P2RX7 antagonist, was equally protective in WKY WT and P2RX7 KO rats, revealing its 'off-target' properties. We identify a novel ATP/P2RX7/K+ efflux-independent and caspase-1/8-dependent pathway for production of IL-1β in rat dendritic cells, which was absent in macrophages. Taken together, these results comprehensively establish that inflammation and autoimmunity in glomerulonephritis is independent of P2RX7 and reveals the off-target properties of drugs previously known as selective P2RX7 antagonists. Rat mononuclear phagocytes may be able to utilise an 'alternative inflammasome' pathway to produce IL-1β independently of P2RX7, which may account for the susceptibility of P2RX7 KO rats to inflammation and autoimmunity in glomerulonephritis. This article is protected by copyright. All rights reserved.
Issue Date: 3-Mar-2022
Date of Acceptance: 28-Feb-2022
URI: http://hdl.handle.net/10044/1/95974
DOI: 10.1002/path.5890
ISSN: 0022-3417
Publisher: Pathological Society of Great Britain and Ireland
Journal / Book Title: Journal of Pathology
Volume: 257
Issue: 3
Copyright Statement: © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Wellcome Trust
Kidney Research UK
Medical Research Council (MRC)
Medical Research Council (MRC)
Funder's Grant Number: 092523/Z/10/Z
RP9/2013
MR/N01121X/1
MR/M018733/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
Pathology
P2RX7
inflammasome
NLRP3
IL-1 beta
glomerulonephritis
vasculitis
caspase-1
autoimmunity
inflammation
EXPERIMENTAL CRESCENTIC GLOMERULONEPHRITIS
GLOMERULAR-BASEMENT-MEMBRANE
P2X(7) RECEPTOR
INTERLEUKIN-1-BETA MATURATION
MEDIATED GLOMERULONEPHRITIS
IL-1-BETA RELEASE
ACTIVATION
RAT
INJURY
MODEL
IL-1β
NLRP3
P2RX7
autoimmunity
caspase-1
glomerulonephritis
inflammasome
inflammation
vasculitis
Adenosine Triphosphate
Animals
Caspase 1
Caspases
Glomerulonephritis
Inflammasomes
Inflammation
Interleukin-1beta
NLR Family, Pyrin Domain-Containing 3 Protein
Rats
Rats, Inbred WKY
Receptors, Purinergic P2X7
Vasculitis
Animals
Rats, Inbred WKY
Rats
Glomerulonephritis
Vasculitis
Inflammation
Caspases
Caspase 1
Adenosine Triphosphate
Interleukin-1beta
Receptors, Purinergic P2X7
Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
IL-1β
NLRP3
P2RX7
autoimmunity
caspase-1
glomerulonephritis
inflammasome
inflammation
vasculitis
Pathology
1103 Clinical Sciences
Publication Status: Published online
Conference Place: England
Open Access location: https://onlinelibrary.wiley.com/doi/10.1002/path.5890
Online Publication Date: 2022-03-03
Appears in Collections:Department of Immunology and Inflammation
Faculty of Medicine



This item is licensed under a Creative Commons License Creative Commons