IL11 Activates Pancreatic Stellate Cells and Causes Pancreatic Inflammation, Fibrosis and Atrophy in a Mouse Model of Pancreatitis

Abstract

Interleukin-11 (IL11) is important for fibrosis and inflammation, but its role in the pancreas is unclear. In pancreatitis, fibrosis, inflammation and organ dysfunction are associated with pancreatic stellate cell (PSC)-to-myofibroblast transformation. Here, we show that IL11 stimulation of PSCs, which specifically express IL11RA in the pancreas, results in transient STAT3 phosphorylation, sustained ERK activation and PSC activation. In contrast, IL6 stimulation of PSCs caused sustained STAT3 phosphorylation but did not result in ERK activation or PSC transformation. Pancreatitis factors, including TGFβ, CTGF and PDGF, induced IL11 secretion from PSCs and a neutralising IL11RA antibody prevented PSC activation by these stimuli. This revealed an important ERK-dependent role for autocrine IL11 activity in PSCs. In mice, IL11 was increased in the pancreas after pancreatic duct ligation, and in humans, IL11 and IL11RA levels were elevated in chronic pancreatitis. Following pancreatic duct ligation, administration of anti-IL11RA to mice reduced pathologic (ERK, STAT, NF-κB) signalling, pancreatic atrophy, fibrosis and pro-inflammatory cytokine (TNFα, IL6 and IL1β) levels. This is the first description of IL11-mediated activation of PSCs, and the data suggest IL11 as a stromal therapeutic target in pancreatitis.

Structures of the interleukin 11 signalling complex reveal dynamics of gp130 extracellular domains and the inhibitory mechanism of a cytokine variant

“…Inhibition of IL-11 signalling has been shown to provide therapeutic benefit in models of arthritis, multiple sclerosis, neointimal hyperplasia, multiple fibrotic diseases, and gastrointestinal cancers [9][10][11]13,17,21,22,25,39,40 . Current IL-11 signalling inhibitors include IL-11 mutants 41,42 and antibodies against either IL-11 9,21,43 or IL-11Rα 11,[44][45][46] . However, mechanistic understanding of their modes of action is limited in the absence of detailed molecular understanding of the IL-11 signalling complex.…”

Current Trends and Research Hotspots in Pancreatic Stellate Cells: A Bibliometric Study

“…Chronic hyperglycemia can activate PSCs and promote the interaction between PSCs and pancreatic cancer cells ( 10 ). Activated PSCs play a crucial role in the development of pathological pancreatic fibrosis ( 11 , 12 ), which characterizes chronic pancreatitis ( 13 , 14 ) and pancreatic cancer-associated desmoplastic reaction ( 7 , 15 ). Therefore, chronic pancreatitis and pancreatic cancer can be treated using anti-fibrotic agents, such as vitamin analogs, targeting PSCs ( 16 ).…”

Thioredoxin-interacting protein deficiency protects against severe acute pancreatitis by suppressing apoptosis signal-regulating kinase 1

“…The damage of pancreatic tissue triggers the activation of PSC, and prompts immune cells and pancreatic acinar cells to secrete inflammatory mediators, which promote the development of AP [ 32 , 33 ]. PSC activation is increasingly recognized as important in pancreatitis, involving many signaling pathways, including ERK, NF-κB, and Ca signaling [ 8 , 34 – 36 ]. Activated PSCs also secrete the neutrophil chemokine IL-8 and macrophage chemoattractant protein-1 (MCP-1) and express intracellular adhesion molecule-1 (ICAM-1) [ 36 , 37 ], suggesting that activated PSCs may be involved in exacerbating pancreatic inflammation by recruiting inflammatory cells.…”