Gamez-Belmonte, ReyesHernandez-Chirlaque, CristinaSanchez de Medina, FerminMartinez-Augustin, Olga2023-01-252023-01-252018-09-09Gámez-Belmonte R, Hernández-Chirlaque C, Sánchez de Medina F, Martínez-Augustin O. Experimental acute pancreatitis is enhanced in mice with tissue nonspecific alkaline phoshatase haplodeficiency due to modulation of neutrophils and acinar cells. Biochim Biophys Acta Mol Basis Dis. 2018 Nov;1864(11):3769-3779.http://hdl.handle.net/10668/12995Tissue nonspecific alkaline phosphatase (TNAP) has a well established role in bone homeostasis and in hepatic/biliary conditions. In addition, TNAP is expressed in the inflamed intestine and is relevant to T and B lymphocyte function. TNAP KO mice are only viable for a few days, but TNAP+/- haplodeficient mice are viable. Acute pancreatitis was induced by repeated caerulein injection in WT and TNAP+/- mice. TNAP+/- mice presented an increased expression of Cxcl2, Ccl2, Selplg (P-selectin ligand), Il6 and Il1b in the pancreas. Freshly isolated acinar cells showed a dramatic upregulation of Cxcl1, Cxcl2, Ccl2, Il6, Selpg or Bax in both pancreatitis groups. TNAP+/- cells displayed a 2-fold higher expression of Cxcl2, and a smaller increase in Il6. These findings could be partly replicated by in vitro treatment of primary acinar cells with caerulein. Furthermore, the proinflammatory effect on acinar cells could be partially reproduced in wild type cells treated with the TNAP inhibitor levamisole. TNAP mRNA levels were also markedly upregulated by pancreatitis in acinar cells. Neutrophil infiltration (MRP8+ cells) and activation (IL-6 and TNF production in LPS treated primary neutrophils) were increased in TNAP+/- vs WT mice. Neutrophil depletion greatly attenuated inflammation, indicating that this cell type is mainly responsible for the higher inflammatory status of TNAP+/- mice. In conclusion, our results show that altered TNAP expression results in heightened pancreatic inflammation, which may be explained by an augmented response of neutrophils and by a higher sensitivity of acinar cells to caerulein injury.enAcinar cellsAcute pancreatitisAlkaline phosphataseCaeruleinNeutrophilsAcinar CellsAlkaline PhosphataseAnimalsCeruletideDisease Models, AnimalHumansLevamisoleMaleMiceMice, Inbred C57BLMice, TransgenicNeutrophilsPancreasPancreatitisRNA, MessengerUp-Regulationresearch article30251694Restricted AccessARN MensajeroCeruletidaCélulas acinaresFosfatasa alcalinaLevamisolModelos animales de enfermedadNeutrófilosPancreatitisRatones endogámicos C57BL10.1016/j.bbadis.2018.09.0091879-260Xhttps://doi.org/10.1016/j.bbadis.2018.09.009