A critical role for Akt1 signaling in acute pancreatitis progression†.

Acute pancreatitis (AP) is an inflammatory disease of the pancreas that causes significant morbidity and mortality worldwide. Unfortunately, there is no specific treatment available to date. Several studies have previously shown that inhibitors of the PI3K/Akt axis downregulate the degree of inflammation in animal models of AP. However, studies on in vivo side-effects of such inhibitors are still lacking. In a recent issue of The Journal of Pathology, Chen, Malagola et al investigated if inhibition of Akt signaling plays a negative role in the regenerative phase of AP. They showed that treating AP mice with an Akt inhibitor (MK2206) impaired acinar regeneration and increased the development of acinar-to-ductal metaplasia. This is the first study to highlight the negative impact of an Akt inhibitor on cellular regeneration while simultaneously inhibiting inflammation in AP. The authors also suggested combining Akt activators to recover pancreatic regeneration. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Cholesterol metabolism promotes B-cell positioning during immune pathogenesis of chronic obstructive pulmonary disease.

The development of chronic obstructive pulmonary disease (COPD) pathogenesis remains unclear, but emerging evidence supports a crucial role for inducible bronchus-associated lymphoid tissue (iBALT) in disease progression. Mechanisms underlying iBALT generation, particularly during chronic CS exposure, remain to be defined. Oxysterol metabolism of cholesterol is crucial to immune cell localization in secondary lymphoid tissue. Here, we demonstrate that oxysterols also critically regulate iBALT generation and the immune pathogenesis of COPD In both COPD patients and cigarette smoke (CS)-exposed mice, we identified significantly upregulated CH25H and CYP7B1 expression in airway epithelial cells, regulating CS-induced B-cell migration and iBALT formation. Mice deficient in CH25H or the oxysterol receptor EBI2 exhibited decreased iBALT and subsequent CS-induced emphysema. Further, inhibition of the oxysterol pathway using clotrimazole resolved iBALT formation and attenuated CS-induced emphysema in vivo therapeutically. Collectively, our studies are the first to mechanistically interrogate oxysterol-dependent iBALT formation in the pathogenesis of COPD, and identify a novel therapeutic target for the treatment of COPD and potentially other diseases driven by the generation of tertiary lymphoid organs.