Objective Chronic pancreatitis (CP) and autoimmune pancreatitis (AIP) are characterised by different inflammatory processes. If pancreatic inflammation is a prerequisite for autoimmunity is still unclear. AIP is considered mostly a T cell-mediated disease; however, in induction of CP, macrophages play a pivotal role. p21—a member of cyclin-dependent kinase inhibitors—can influence inflammatory processes, in particular can regulate T cell activation and promote macrophage development. We therefore examined the role of p21-mediated inflammation in AIP.
Design We intercrossed lymphotoxin (LT) overexpressing mice (Tg(Ela1-LTa,b))—a model to study AIP development—with p21-deficient mice. Furthermore, we characterised p21 expression in human AIP and non-AIP specimens.
Results p21 deficiency in LT mice (LTp21−/−) prevented early pancreatic injury and reduced inflammation. In acinar cells, diminished proliferation and abrogated activation of non-canonical nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway was observed. In contrast, 12-month-old LT mice with and without p21 had similar inflammatory signatures and T–B cell infiltration. Interestingly, LT and LTp21−/− mice had comparable tertiary lymphoid organs (TLOs), autoantibodies and elevated IgG levels. However, acinar cell proliferation, acinar-to-ductal metaplasia and acinar non-canonical NF-κB pathway activation remained impaired in LTp21−/− pancreata.
Conclusions Our findings indicate that p21 is crucial for pancreatic inflammation in LT-driven pancreatic injury. p21 is involved in early acinar secretion of inflammatory mediators that attract innate immune cells. However, p21 is not essential for humoral immune response, accountable for autoimmunity. Remarkably, p21 renders acinar cells less susceptible to proliferation and transdifferentiation. We therefore suggest that AIP can also develop independent of chronic inflammatory processes.
- experimental pancreatitis
- cell cycle
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GMS, TR and LP contributed equally.
MH and RG contributed equally.
Contributors GS and RG designed and performed the experiments, analysed the data and wrote the manuscript. TR LP and SSt performed the experiments. CV provided human material and participated in paper writing and pathological analysis of tissues and editing the manuscript. SSe contributed with analysis of mouse tissues. AG, SSo, ED and MH participated in editing the manuscript and provided conceptual advice.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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