Identification of novel immune-related targets mediating disease progression in acute pancreatitis

Abstract

IntroductionAcute pancreatitis (AP) is an inflammatory disease with very poor outcomes. However, the order of induction and coordinated interactions of systemic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS) and the potential mechanisms in AP are still unclear.MethodsAn integrative analysis was performed based on transcripts of blood from patients with different severity levels of AP (GSE194331), as well as impaired lung (GSE151572), liver (GSE151927) and pancreas (GSE65146) samples from an AP experimental model to identify inflammatory signals and immune response-associated susceptibility genes. An AP animal model was established in wild-type (WT) mice and Tlr2-deficient mice by repeated intraperitoneal injection of cerulein. Serum lipase and amylase, pancreas impairment and neutrophil infiltration were evaluated to assess the effects of Tlr2 in vivo.ResultsThe numbers of anti-inflammatory response-related cells, such as M2 macrophages (P = 3.2 × 10–3), were increased with worsening AP progression, while the numbers of pro-inflammatory response-related cells, such as neutrophils (P = 3.0 × 10–8), also increased. Then, 10 immune-related AP susceptibility genes (SOSC3, ITGAM, CAMP, FPR1, IL1R1, TLR2, S100A8/9, HK3 and MMP9) were identified. Finally, compared with WT mice, Tlr2-deficient mice exhibited not only significantly reduced serum lipase and amylase levels after cerulein induction but also alleviated pancreatic inflammation and neutrophil accumulation.DiscussionIn summary, we discovered SIRS and CARS were stimulated in parallel, not activated consecutively. In addition, among the novel susceptibility genes, TLR2might be a novel therapeutic target that mediates dysregulation of inflammatory responses during AP progression.

Identification of Biomarkers Associated with Oxidative Stress and Immune Cells in Acute Pancreatitis

“…Toll-like receptors (Tlr) signaling pathway may ship an important role in ap that attenuates organ damage and pancreatic neutrophil accumulation when Tlr2 is knocked down. 43 Another study showed that the Toll-like receptor 9/MyD88/TRAF6/NF-κB signaling pathway plays an important role in intestinal mucosal barrier injury in SAP. 44 Previous studies have verified that the injury of non-pancreatic organs in AP is primarily caused by apoptosis.…”

Immune-Related Genes can Serve as Potential Biomarkers for Predicting Severe Acute Pancreatitis

“…Moreover, CAMP encodes a member of the antimicrobial peptide family, which plays an important role in innate immune defense against viruses and has functions in regulating inflammatory response 40 . CAMP has been reported to be associated with the pathophysiological phenotype of AP 41 . Taken together, these studies revealed the correlation of these genes with AP severity, which further support our findings.…”

Ferroptosis exacerbates hyperlipidemic acute pancreatitis by enhancing lipid peroxidation and modulating the immune microenvironment

“…During the progression of AP, severe necrosis occurs due to the progressive migration of macrophages into pancreatic tissue, and helper T-cell 2 (Th2) cells begin to exert proinflammatory effects and drive T cells to differentiate into Th2 cells, further exacerbating inflammation [ 75 ]. Therefore, a severe imbalance in Th1/Th2 cells in tissues and a decrease in CD4 + T cells in the peripheral blood can be essential indicators for predicting SAP [ 76 ]. Furthermore, helper T-cell 17 (Th17) cells amplify the inflammatory cascade response in AP and initiate SIRS [ 77 ].…”