RT Journal Article
T1 Experimental acute pancreatitis is enhanced in mice with tissue nonspecific alkaline phoshatase haplodeficiency due to modulation of neutrophils and acinar cells.
A1 Gamez-Belmonte, Reyes
A1 Hernandez-Chirlaque, Cristina
A1 Sanchez de Medina, Fermin
A1 Martinez-Augustin, Olga
K1 Acinar cells
K1 Acute pancreatitis
K1 Alkaline phosphatase
K1 Caerulein
K1 Neutrophils
AB Tissue 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.
PB Elsevier BV
YR 2018
FD 2018-09-09
LK http://hdl.handle.net/10668/12995
UL http://hdl.handle.net/10668/12995
LA en
NO Gámez-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.
NO This work was supported by funds from the Ministry of Economy and Competitivity, partly with Fondo Europeo de Desarrollo Regional FEDER funds [SAF2017-88457-R, AGL2017-85270-R, BFU2014-57736-P, AGL2014-58883-R] and by Junta de Andalucía [CTS235, CTS164]. CHC and RGB were supported by the University of Granada (Contrato Puente Program - Plan Propio) and the Ministry of Education [Spain], respectively. CIBERehd is funded by Instituto de Salud Carlos III.
DS RISalud
RD Apr 17, 2025