TY - JOUR
T1 - Interleukin 22 disrupts pancreatic function in newborn mice expressing IL-23
AU - Chen, Lili
AU - Strohmeier, Valentina
AU - He, Zhengxiang
AU - Deshpande, Madhura
AU - Catalan-Dibene, Jovani
AU - Durum, Scott K.
AU - Moran, Thomas M.
AU - Kraus, Thomas
AU - Xiong, Huabao
AU - Faith, Jeremiah J.
AU - Sodhi, Chhinder P.
AU - Hackam, David J.
AU - Lira, Sergio A.
AU - Furtado, Glaucia C.
N1 - Funding Information:
We thank Dr. Maria C. Lafaille for comments, Dr. Ana Valbuena for help with the Luminex assay, and Dr. Kevin Kelley and the Mouse Genetics and Gene Targeting CoRE Facility for assistance in generation of gene-modified mice. This work was supported by a grant from the National Institutes of Health (R01DK110352) to S.A.L. L.C. was supported by a Career Development Award (634253) from the Crohn’s and Colitis Foundation of America (CCFA).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Neonatal inflammatory diseases are associated with severe morbidity, but the inflammatory factors underlying them and their potential effector mechanisms are poorly defined. Here we show that necrotizing enterocolitis in neonate mice is accompanied by elevation of IL-23 and IL-22 and decreased production of pancreatic enzymes. These phenotypes are mirrored in neonate mice overexpressing IL-23 in CX3CR1+ myeloid cells or in keratinocytes. The mice fail to grow and die prematurely, displaying systemic inflammation, nutrient malabsorption and decreased expression of intestinal and pancreatic genes mediating digestion and absorption of carbohydrates, proteins, and lipids. Germ-free environment improves, and genetic ablation of IL-22 restores normal growth in mice overexpressing IL-23. Mechanistically, IL-22 acts directly at the level of pancreatic acinar cells to decrease expression of the pancreas associated transcription factor 1a (PTF1a). These results show that augmented production of IL-23 and IL-22 in early life has a negative impact on pancreatic enzyme secretion and food absorption.
AB - Neonatal inflammatory diseases are associated with severe morbidity, but the inflammatory factors underlying them and their potential effector mechanisms are poorly defined. Here we show that necrotizing enterocolitis in neonate mice is accompanied by elevation of IL-23 and IL-22 and decreased production of pancreatic enzymes. These phenotypes are mirrored in neonate mice overexpressing IL-23 in CX3CR1+ myeloid cells or in keratinocytes. The mice fail to grow and die prematurely, displaying systemic inflammation, nutrient malabsorption and decreased expression of intestinal and pancreatic genes mediating digestion and absorption of carbohydrates, proteins, and lipids. Germ-free environment improves, and genetic ablation of IL-22 restores normal growth in mice overexpressing IL-23. Mechanistically, IL-22 acts directly at the level of pancreatic acinar cells to decrease expression of the pancreas associated transcription factor 1a (PTF1a). These results show that augmented production of IL-23 and IL-22 in early life has a negative impact on pancreatic enzyme secretion and food absorption.
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U2 - 10.1038/s41467-019-12540-8
DO - 10.1038/s41467-019-12540-8
M3 - Article
C2 - 31586069
AN - SCOPUS:85072909900
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4517
ER -