Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN

Abstract

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-6Ra, and in vitro treatment with IL-6 blocked macrophage proliferation. Furthermore, proinflammatory macrophages were expanded during inflammation in IL-6 2/2 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.

iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling

“…Moreover, transactivation of the EGFR by other factors, such as CXCL1 and TNF-like weak inducer of apoptosis (TWEAK) (60,61), and most likely also via iRhom2/ADAM17, could also contribute to EGFR activation in Fcgr2b -/-kidneys. In addition, other iRhom2/ADAM17 substrates, such as IL-6R, may also contribute to renal damage in this model (62)(63)(64), which requires future study.…”

Biological effects of interleukin-6: Clinical applications in autoimmune diseases and cancers

“…Interestingly, treatment with anti-IL-6R or anti-IL-6 exacerbated renal damage in the murine model of nephrotoxic nephritis, while treatment with soluble gp130-Fc fusion protein did not [48]. The study also demonstrated that macrophages, which mediated the pathogenesis of nephrotoxic nephritis, accumulated in the kidney, expressed high levels of IL-6R and proliferated in IL-6-deficient mice; treatment with IL-6 strongly Page 16 of 64 A c c e p t e d M a n u s c r i p t 16 inhibited macrophage proliferation [48].…”

IL-6 Trans-Signaling Drives Murine Crescentic GN

“…53,54 In line with this, deletion of the membrane-standing IL-6 receptor from myeloid cells required for classic signaling greatly facilitated the generation of proinflammatory M1-like macrophages and thus aggravated disease in NTN on a C57Bl/6 background. 10 Using the same anti-IL-6 antibody, we failed to detect significant differences in outcome of NTN in our BALB/c mice. Conceivably, this difference relates to the choice of mouse strains, given that the BALB/c Th2-prone background leads to relatively mild macrophage and T-cell responses compared with mice on the C57Bl/6 background.…”

“…11,34,35 However, at the same time yet other reports noted a protective role of IL-6 in rat NTN 9 or conversely worsening of NTN in C57Bl/6 mice by IL-6 antagonism. 10 While it certainly is conceivable that differences in the experimental design and model of renal disease accounted for some of these discrepancies, it has also been shown that IL-6 can have a dichotomous role in renal disease. For example, in acute kidney injury, IL-6 contributes to early leukocyte-mediated damage but subsequently mediates tubular regeneration.…”

“…Likewise, IL-6 inhibition by either an IL-6-or an IL-6-receptor (IL-6R)-specific antibody aggravated NTN in C57Bl/6 mice leading to increased macrophage activity. 10 However, research in models of systemic lupus erythematosus (SLE) arrived at an opposite conclusion. In one study IL-6 infusion exerted an aggravating effect on GN.…”