Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN
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Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN. / Luig, Michael; Kluger, Malte A; Goerke, Boeren; Meyer, Matthias C; Nosko, Anna; Yan, Isabell; Scheller, Jürgen; Mittrücker, Hans-Willi; Rose-John, Stefan; Stahl, Rolf A K; Panzer, Ulf; Steinmetz, Oliver M.
in: J AM SOC NEPHROL, Jahrgang 26, Nr. 7, 05.02.2015, S. 1597-1607.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN
AU - Luig, Michael
AU - Kluger, Malte A
AU - Goerke, Boeren
AU - Meyer, Matthias C
AU - Nosko, Anna
AU - Yan, Isabell
AU - Scheller, Jürgen
AU - Mittrücker, Hans-Willi
AU - Rose-John, Stefan
AU - Stahl, Rolf A K
AU - Panzer, Ulf
AU - Steinmetz, Oliver M
N1 - Copyright © 2015 by the American Society of Nephrology.
PY - 2015/2/5
Y1 - 2015/2/5
N2 - IL-6 can mediate proinflammatory effects, and IL-6 receptor (IL-6R) blockade as a treatment for inflammatory diseases has entered clinical practice. However, opposing effects of IL-6 have been observed in models of GN. Although IL-6 is proinflammatory in murine lupus nephritis, protective effects have been observed for IL-6 in the nephrotoxic nephritis (NTN) model of acute crescentic GN. In light of the potential dangers of IL-6-directed treatment, we studied the mechanisms underlying the contradictory findings in GN. IL-6 can signal through the membrane-bound IL-6R, which is expressed only on hepatocytes and certain leukocytes (classic), or through the soluble IL-6R, which binds the ubiquitously expressed gp130 (alternative). Preemptive treatment of mice with anti-IL-6R or anti-IL-6 worsened NTN, whereas selective blockade of alternative IL-6 signaling by the fusion protein sgp130Fc did not. FACS analysis of mouse spleen cells revealed proinflammatory macrophages express the highest levels of IL-6Rα, and in vitro treatment with IL-6 blocked macrophage proliferation. Furthermore, proinflammatory macrophages were expanded during inflammation in IL-6(-/-) mice. Late application of anti-IL-6 after establishment of adaptive nephritogenic immunity was sufficient to aggravate NTN within 2.5 days, a period when macrophages are active. Finally, NTN was aggravated in mice with macrophage-specific impairment of IL-6 classic signaling, coincident with enhanced macrophage proliferation and accumulation in the kidney. Our data thus reveal a novel mechanism in which IL-6-mediated dampening of macrophage activation protects tissues from overshooting immune responses. This finding has important implications for potential IL-6-directed therapies and supports the careful choice of recipient patients and timing.
AB - IL-6 can mediate proinflammatory effects, and IL-6 receptor (IL-6R) blockade as a treatment for inflammatory diseases has entered clinical practice. However, opposing effects of IL-6 have been observed in models of GN. Although IL-6 is proinflammatory in murine lupus nephritis, protective effects have been observed for IL-6 in the nephrotoxic nephritis (NTN) model of acute crescentic GN. In light of the potential dangers of IL-6-directed treatment, we studied the mechanisms underlying the contradictory findings in GN. IL-6 can signal through the membrane-bound IL-6R, which is expressed only on hepatocytes and certain leukocytes (classic), or through the soluble IL-6R, which binds the ubiquitously expressed gp130 (alternative). Preemptive treatment of mice with anti-IL-6R or anti-IL-6 worsened NTN, whereas selective blockade of alternative IL-6 signaling by the fusion protein sgp130Fc did not. FACS analysis of mouse spleen cells revealed proinflammatory macrophages express the highest levels of IL-6Rα, and in vitro treatment with IL-6 blocked macrophage proliferation. Furthermore, proinflammatory macrophages were expanded during inflammation in IL-6(-/-) mice. Late application of anti-IL-6 after establishment of adaptive nephritogenic immunity was sufficient to aggravate NTN within 2.5 days, a period when macrophages are active. Finally, NTN was aggravated in mice with macrophage-specific impairment of IL-6 classic signaling, coincident with enhanced macrophage proliferation and accumulation in the kidney. Our data thus reveal a novel mechanism in which IL-6-mediated dampening of macrophage activation protects tissues from overshooting immune responses. This finding has important implications for potential IL-6-directed therapies and supports the careful choice of recipient patients and timing.
U2 - 10.1681/ASN.2014060620
DO - 10.1681/ASN.2014060620
M3 - SCORING: Journal article
C2 - 25655068
VL - 26
SP - 1597
EP - 1607
JO - J AM SOC NEPHROL
JF - J AM SOC NEPHROL
SN - 1046-6673
IS - 7
ER -