Genetics, Cell Biology, and Pathophysiology of Pancreatitis

Abstract

Since the discovery of the first trypsinogen mutation in families with hereditary pancreatitis, pancreatic genetics has made rapid progress. The identification of mutations in genes involved in the digestive protease-antiprotease pathway has lent additional support to the notion that pancreatitis is a disease of autodigestion. Clinical and experimental observations have provided compelling evidence that premature intrapancreatic activation of digestive proteases is critical in pancreatitis onset. However, disease course and severity are mostly governed by inflammatory cells that drive local and systemic immune responses. In this article, we review the genetics, cell biology, and immunology of pancreatitis with a focus on protease activation pathways and other early events.

Keywords: Cell Death; Genetics; Inflammation; Pancreatitis; Trypsinogen.

Figure 1.

Genetic risk factors associated with the trypsin-dependent pathological pathway. See text for details.

Figure 2.

Genetic risk factors associated with the ductal pathological pathway. See text for details.

Figure 3.

Trypsinogen activation and cell death in pancreatic acinar cells. Intracellular trypsinogen activation is an early event at the onset of acute experimental pancreatitis. Supramaximal secretagogue-receptor stimulation or activation of bile salt receptors leads to an un-physiological peak-plateau calcium signal. This results in disrupted exocytosis of zymogen granules, secretory blockage, zymogen retention and formation of endocytic vacuoles, which contain trypsin and trypsinogen, taken up from the extracellular space. Those vacuoles co-localize and fuse with lysosomes containing cathepsin B, which in turn transforms trypsinogen into active trypsin. Due to increasing instability endocytic vacuoles often rupture, releasing trypsin and cathepsin B into the cytosol. Active trypsin is thought to induce mainly apoptosis, a silent form of cell death, which suppresses inflammation. In contrast, if the pathological calcium release cannot be contained, rapid energy depletion occurs and cells undergo necrosis during which the plasma membrane becomes leaky and cellular components e.g. DNA or mitochondria reach the extracellular space. Those will be recognized by leukocytes, which will be activated via the inflammasome signaling pathway. IL1β- and TNFα-release as well as pyroptosis occur. If TNFα reaches the basolateral membrane of previously unaffected or slightly damaged acinar cells it can induce another form of programmed cell death, called necroptosis.

Figure 4:

NFκB pathway in pancreatic acinar cells. The early activation of NFκB follows the same time pattern as trypsinogen activation. Both are induced by cytoplasmatic Ca²⁺ influx, but NFκB did not depend on trypsinogen activation. The phosphorylation of IκBα, followed by proteasomal degradation and the nuclear translocation of NFκB (p65/p50) occurs in parallel to protease activation. NFκB as transcription factor acts in two directions; first the transcriptions of pro-inflammatory genes like IL6 or TNFα to initiate the immune response and second the transcription of pro-survival genes. Therefore NFκB can directly influence protease activity to protect cells by the up-regulation of Spi2A, a serine protease inhibitor.

Figure 5:

NFκB activation in inflammatory cells. There are multiple pathways how NFκB could be activated within leukocytes; here are the major pathways which play a role during acute pancreatitis. Cytokines like IL1β or TNFα as well as DAMP signals acting via Toll-like receptors can induce the translocation of p65/p50 into the nucleus. In leukocytes the majority of inflammatory mediators are under the control of NFκB: cytokines, chemokines, adhesion molecules and components of the inflammasome pathway. Leukocyte mediated NFκB activation enhances the immune response in a very prominent manner and therefore has a different role in pancreatitis compared to NFκB activation within acinar cell.