Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer

Abstract

Inflammation and autophagy are cellular defense mechanisms. When these processes are deregulated (deficient or overactivated) they produce pathologic effects, such as oxidative stress, metabolic impairments, and cell death. Unresolved inflammation and disrupted regulation of autophagy are common features of pancreatitis and pancreatic cancer. Furthermore, obesity, a risk factor for pancreatitis and pancreatic cancer, promotes inflammation and inhibits or deregulates autophagy, creating an environment that facilitates the induction and progression of pancreatic diseases. However, little is known about how inflammation, autophagy, and obesity interact to promote exocrine pancreatic disorders. We review the roles of inflammation and autophagy, and their deregulation by obesity, in pancreatic diseases. We discuss the connections among disordered pathways and important areas for future research.

Figure 1

Inflammation in acute pancreatitis. Acinar cells respond to initial insult by activating transcription factors such as NF-κB, activator protein-1 (AP-1), and NFAT, leading to production of cytokines and other mediators that initiate the inflammatory response. Inflammation is also induced by release of DAMPs from damaged or dying cells, which activates inflammasomes. The inflammatory mediators recruit neutrophils, macrophages, and T cells into the pancreas, leading to cytokine storm and systemic inflammation. In most cases, pancreatic injury and inflammation resolves, but if perpetuated it can lead to potentially fatal SIRS and multiple organ dysfunction (MODS). Dashed lines indicate pathways that are likely but not proven in pancreatitis.

Figure 2

Inflammation in PDAC. Activation of Kras in pancreatic epithelial cells promotes production of inflammatory mediators (including IL-6 and IL-11, which activate STAT3 in an autocrine manner) or recruits myeloid cells that produce IL-6 and sIL-6R to activate STAT3 in a paracrine manner. NF-κB also can be activated in an autocrine or paracrine manner by TNFα and IL-1α, creating a positive-feedback loop to maintain the tumor’s inflammatory microenvironment. Inflammation-induced activation of STAT3 and NF-κB promotes cell survival, proliferation, and the EMT, which contribute to initiation and progression of PDAC. Pancreatic neoplastic cells that express oncogenic Kras also produce the inflammatory cytokine granulocyte-macrophage colony–stimulating factor (GM-CSF), leading to recruitment of myeloid progenitor cells and their subsequent differentiation into MDSCs, which suppress the immune surveillance function of CD8⁺ T cells. COX2, cyclooxygenase 2; MMP, matrix metalloproteinase.

Figure 3

Dual role of autophagy in PDAC development. PDAC cells require efficient autophagy to survive hypoxia, nutrient deprivation, metabolic stress, and exposure to chemotherapeutic agents. Basal autophagy therefore promotes growth of PDACs by maintaining functional mitochondria, reducing ROS and DNA damage, supplying tricarboxylic acid (TCA) cycle metabolites, and facilitating glycolysis. In contrast, autophagy suppresses PDAC initiation: it limits ROS production, genomic damage, cell injury, and inflammation; and eliminates oncogenic aggregates of p62, to prevent transformation of epithelial cells.

Figure 4

Autophagy limits inflammation. Pancreatitis and obesity each reduce the efficacy of, or lead to defects in, autophagy. Reduced autophagy promotes inflammation and tumorigenesis in patients with pancreatitis or obesity.