IL-1β promotes tubulointerstitial injury in  MPO-ANCA-associated glomerulonephritis .
BACKGROUND
It is widely accepted that tubulointerstitial injury (TII) is caused by glomerular injury (GI) in glomerular diseases. Glomerular endocapillary inflammation may result in crescent formation and exuded protein leakage, which may induce TII in antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCAGN). However, some reports have indicated a glomerulonephritis-independent mechanism of TII in ANCAGN. The aim of this study was to determine the principle cytokines correlated with TII severity and to elucidate a characteristic mechanism for TII in ANCAGN.


METHODS
28 myeloperoxidase-ANCA-positive ANCAGN patients were enrolled, and their kidney biopsy specimens were histologically evaluated with regard to GI and TII. The mRNA expression of various cytokines was examined in 28 specimens.


RESULTS
Interleukin (IL)-1β was significantly correlated with the severity of TII. The mRNA expression of Toll-like receptor 4 (TLR4) and Nod-like receptor family pyrin domain-containing-3 (NLRP3) also correlated with TII severity. Immunohistochemical analysis demonstrated that TLR4 protein was positively stained in the tubulointerstitial infiltrating cells. NRLP3 protein was detected in macrophages in the severe infiltrating area but was absent or only very faintly expressed in the glomeruli. These results indicated that NLRP3 inflammasome-dependent processing in macrophages releases the mature active form of IL-1β, which may lead to the development and deterioration of TII.


CONCLUSIONS
Sterile inflammation leads to the formation of ANCA-mediated neutrophil extracellular traps (NETs), which may stimulate macrophages and dendritic cells via TLR4 and induce NF-κB-dependent mRNA expression and translation of pro-IL-1β. Simultaneously, damage-associated molecular pattern signals resulting from NETs promote NLRP3 inflammasome-dependent processing and release mature active IL-1β. Sterile inflammation utilizing the NLRP3 inflammasome might be a characteristic reaction limited to the tubulointerstitium. Thus, neutralizing IL-1β may be a promising strategy to suspend the progress of TII and improve the prognosis of chronic kidney disease resulting from ANCAGN. .
Manabu
M
Tashiro
Yoshie
Y
Sasatomi
Renya
R
Watanabe
Maho
M
Watanabe
Katsuhisa
K
Miyake
Yasuhiro
Y
Abe
Tetsuhiko
T
Yasuno
Kenji
K
Ito
Naoko
N
Ueki
Aki
A
Hamauchi
Ritsuya
R
Noda
Satoshi
S
Hisano
Hitoshi
H
Nakashima
D000368:Aged; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000378:metabolism*; D005260:Female; D005921:Glomerulonephritis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000502:physiology*; D007678:Kidney Glomerulus / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009395:Nephritis, Interstitial / Q000378:metabolism* / Q000473:pathology; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D019268:Antibodies, Antineutrophil Cytoplasmic; D058847:Inflammasomes; D053583:Interleukin-1beta; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4