Macrophages-induced IL-18–mediated eosinophilia promotes characteristics of pancreatic malignancy

Abstract

Reports indicate that accumulated macrophages in the pancreas are responsible for promoting the pathogenesis of chronic pancreatitis (CP). Recently, macrophage-secreted cytokines have been implicated in promoting pancreatic acinar-to-ductal metaplasia (ADM). This study aims to establish the role of accumulated macrophage-activated NLRP3-IL-18-eosinophil mechanistic pathway in promoting several characteristics of pancreatic malignancy in CP. We report that in a murine model of pancreatic cancer (PC), accumulated macrophages are the source of NLRP3-regulated IL-18, which promotes eosinophilic inflammation-mediated accumulation to periductal mucin and collagen, including the formation of ADM, pancreatic intraepithelial neoplasia (PanINs), and intraductal papillary mucinous neoplasm. Most importantly, we show improved malignant characteristics with reduced levels of oncogenes in an anti–IL-18 neutralized and IL-18 gene deficient murine model of CP. Last, human biopsies validated that NLRP3-IL-18–induced eosinophils accumulate near the ducts, showing PanINs formation in PC. Taken together, we present the evidence on the role of IL-18–induced eosinophilia in the development of PC phenotype like ADM, PanINs, and ductal cell differentiation in inflammation-induced CP.

Heparanase 2 (Hpa2)- a new player essential for pancreatic acinar cell differentiation

“…This treatment regimen was reported to elicit pancreatic neoplasia [ 37 ] and is based upon the notion that combining the effect of carcinogens with chronic inflammation elicits tumor initiation and growth [ 38 ]. Given the severe morphological alterations of Hpa2-KO pancreas we, nonetheless, reduced the frequency of cerulein treatment from three consecutive days [ 37 ] to only once per week (Fig. 7B ).…”

“…Chronic pancreatitis ( CP) was induced by repetitive intraperitoneal (i.p) administration of cerulein without or with azoxymethane (AOM), each alone and in combination, as described elsewhere [ 37 ]. AOM (10 mg/kg) was administrated i.p in 0.1 ml saline; Cerulein (50 μg/kg) was given by repetitive 6 hourly i.p injections, in 0.1 ml saline, as reported [ 37 ].…”

Precise Photodynamic Therapy by Midkine Nanobody-Engineered Nanoparticles Remodels the Microenvironment of Pancreatic Ductal Adenocarcinoma and Potentiates the Immunotherapy

“…Among the downregulated BPs, IL-18, cellular response to fibroblast growth factor stimulus, and sphingolipid biosynthetic process were significantly affected (Figure S25B). Previous studies − reported that IL-18 and sphingolipid metabolism played important roles in promoting the occurrence and development of PC. In summary, these RNA-seq results indicated that the influence of D4 Nb-PCP NPs plus light irradiation on PDAC cells or TME involved a complex regulatory network and multiple molecular mechanisms of action, which might inhibit tumor progression by affecting tumor biosynthesis, metabolic response, and immune regulation.…”

Allergen-induced NLRP3/caspase1/IL-18 signaling initiate eosinophilic esophagitis and respective inhibitors protect disease pathogenesis

“…Sections of paraffin-embedded mouse esophagus tissue (5 m) were deparaffinized and dehydrated, and staining was performed as previously reported 53 . Antigen retrieval was performed using the Citric Acid-based Antigen Unmasking Solution (Vector labs) method, followed by blocking with 5% normal goat serum to reduce non-specific binding and incubation with specific primary antibodies: anti-F4/80 (1:200, Cell Signaling Technology, 30325S); Rabbit anti-NLRP3 (1:200, Cell Signaling Technology, 15101S); anti-IL-18 (1:200, Invitrogen, HL1859); anti-Cytokeratin antibody (1:400, Cell Signaling Technology, 4545).…”