JMJD3 Is Required for Acute Pancreatitis and Pancreatitis-Associated Lung Injury

Abstract

Acute pancreatitis (AP) can be complicated by inflammatory disorders of remote organs, such as lung injury, in which Jumonji domain-containing protein 3 (JMJD3) plays a vital role in proinflammatory responses. Currently, we found that JMJD3 expression was upregulated in the pancreas and lung in an AP male mouse model, which was also confirmed in AP patients. Further experiments revealed that the upregulation of JMJD3 and proinflammatory effects were possibly exerted by mitochondrial DNA (mtDNA) or oxidized-mtDNA from tissue injury caused by AP. The release of mtDNA and oxidized-mtDNA contributed to the infiltration of inflammatory monocytes in lung injury through the stimulator of IFN genes (STING)/TLR9-NF-κB-JMJD3-TNF-α pathway. The inhibition of JMJD3 or utilization of Jmjd3-cKO mice significantly alleviated pulmonary inflammation induced by AP. Blocking mtDNA oxidation or knocking down the TLR9/STING pathway effectively alleviated inflammation. Therefore, inhibition of JMJD3 or STING/TLR9 pathway blockage might be a potential therapeutic strategy to treat AP and the associated lung injury.

Immune markers of severe acute pancreatitis

“…Three hypotheses exist to explain why systemic injury occurs in SAP [8,9]. The dysregulated and excessive host immune response hypothesis suggests that there is dysregulated activation of DAMPs-NLRP3-inflammasome pathway, with propagation of innate immune cells and their products (e.g., neutrophilic extracellular traps, reactive oxygen species) to the cardiopulmonary system to cause direct toxic injury through tissue damage and local inflammation [15 & , [16][17][18][19]. The capillary leak syndrome hypothesis [20] postulates that marked systemic vascular permeability is the cardinal event leading to circulatory shock and respiratory failure [20].…”