Redefining Interleukin 11 as a regeneration-limiting hepatotoxin

Abstract

37Acetaminophen (APAP) overdose is a leading cause of untreatable liver failure. In the mouse 38 model of APAP-induced liver injury (AILI), the administration of recombinant human 39 interleukin 11 (rhIL11) is protective. Here we show that the beneficial effect of rhIL11 in the 40 mouse is due to its unexpected and paradoxical inhibition of endogenous mouse IL11 activity. 41 Contrary to the accepted paradigm IL11 is a potent hepatotoxin across species, which is secreted 42 from damaged hepatocytes to drive an autocrine loop of NOX4 and JNK-dependent apoptosis. 43Mice with hepatocyte-specific Il11 expression spontaneously develop liver failure whereas those 44 with Il11ra1 deletion are remarkably protected from AILI. Neutralizing anti-IL11R antibodies 45 administered to moribund mice 10 hours following a lethal APAP overdose results in 90% 46 survival that is associated with very large liver regeneration. Our data overturn a misconception, 47 identify a new disease mechanism and suggest IL11 as a therapeutic target for liver regeneration. 49Main text 50 Acetaminophen (N-acetyl-p-aminophenol, APAP) is an over-the-counter analgesic that is 51 commonly taken as an overdose (OD) leading to APAP-induced liver injury (AILI), a major 52 cause of acute liver failure 1 . The antioxidant N-acetyl cysteine (NAC) is beneficial for patients 53 presenting early 2 , but there is no drug-based treatment beyond eight hours post-OD and death 54 can ensue if liver transplantation is not possible 3,4 . 55In hepatocytes, APAP is metabolized to N-Acetyl-p-benzochinonimin (NAPQI) which 56 depletes cellular glutathione (GSH) levels and damages mitochondrial proteins leading to 57 reactive oxygen species (ROS) production and JNK activation 5 . ROS-related JNK activation 58 results in a combination of necrotic, apoptotic and other forms of hepatocyte cell death causing 59 liver failure 1,6,7 . JNK and ASK1 inhibitors have partial protective effects against AILI in mouse 60 models, but this has not translated to the clinic 8,9 . 61Liver regeneration has fascinated humans since the stories of Prometheus and can be 62 truly profound, as seen after partial hepatic resection in rodents and humans 10,11 . However, in the 63 setting of AILI, liver regeneration is persistently suppressed resulting in permanent injury and 64 patient mortality. Targeting the pathways that hinder the liver's extraordinary regenerative 65 capacity may trigger natural regeneration, which could be particularly useful in AILI 12,13 . 66Interleukin 11 (IL11) is a scarcely studied cytokine that is of critical importance for 67 myofibroblast activation and fibrosis of the heart, kidney, lung, and liver [14][15][16] . It is established 68 that IL11 is secreted from injured hepatocytes and Il11 can be detected at high levels in the 69 serum of the mouse model of AILI, where its expression is considered compensatory and 70 cytoprotective 17 . In keeping with this paradigm, administration of recombinant human IL11 71 (rhIL11) is effective in treating the mouse model of A...

Transgenic interleukin 11 expression causes cross-tissue fibro-inflammation and an inflammatory bowel phenotype in mice

“…However, a caveat with these studies is that human IL11 was administered to rodents despite the fact that human IL11 does not activate mouse stromal cells [8]. More recently, we have found that human IL11 unexpectedly acts as an inhibitor of endogenous mouse IL11 activity in the liver [39]. Thus, previous studies in IBD that showed that when human IL11 is injected into mice it protects them from IBD may paradoxically support the opposite conclusion: IL11 is not protective at all, but a driver of IBD.…”

Different roles of interleukin 6 and interleukin 11 in the liver: implications for therapy

“…7 Only very recently, have experiments shown a central role for endogenous and species-matched IL11 in the pathology of fibroinflammatory diseases such as inflammatory bowel disease (IBD), cardiorenal and lung fibrosis, and acute and chronic liver disease. 5,[8][9][10][11] In this review, we examine the roles IL6 and IL11 in the liver and discuss the therapeutic opportunities these cytokines may provide for liver disease. While the older literature proposed these two cytokines have overlapping and redundant roles in the liver, we discuss recent data that challenges longheld assumptions.…”

Autocrine IL11 cis-signaling in hepatocytes is an initiating nexus between lipotoxicity and non-alcoholic steatohepatitis

“…Given the lack of IL6R in human hepatocytes we needed to employ a synthetic IL6 trans-signaling construct (hyperIL6) to activate IL6 signaling and compared this with a synthetic IL11 trans-signaling complex (hyperIL11). HyperIL11, like IL11 itself [6], activated ERK and JNK in a dose-dependent manner (2.5 ng/ml to 20 ng/ml). In contrast, IL6 trans-signaling did not activate non-canonical signaling pathways but instead dose-dependently induced STAT3 activation ( Fig.…”

“…Interleukin 11 (IL11) is a fibrogenic factor [1][2][3][4] that is elevated in fibrotic precision-cut liver slices across species [5]. IL11 has recently been shown to have negative effects on hepatocyte function after toxic liver insult [6] and, directly or indirectly, contributes to nonalcoholic steatohepatitis (NASH) pathologies [7]. At the other end of the spectrum, a number of earlier publications suggest that IL11 is protective in mouse models of ischemic-, infective-or toxin-induced liver damage [8][9][10][11][12][13].…”

“…At the other end of the spectrum, a number of earlier publications suggest that IL11 is protective in mouse models of ischemic-, infective-or toxin-induced liver damage [8][9][10][11][12][13]. However, it is now apparent that the recombinant human IL11 (rhIL11) reagent used in these earlier studies is ineffective in the mouse [6] and the question as to the true biological effect of IL11 in the liver, specifically in hepatocytes, remains open.…”