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Blocking NF-κB Activation in Ly6c + Monocytes Attenuates Necrotizing Enterocolitis.
- Source :
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The American journal of pathology [Am J Pathol] 2019 Mar; Vol. 189 (3), pp. 604-618. Date of Electronic Publication: 2018 Dec 27. - Publication Year :
- 2019
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Abstract
- Necrotizing enterocolitis (NEC) is a devastating disease affecting premature infants with intestinal inflammation and necrosis. The neonatal intestinal inflammatory response is rich in macrophages, and blood monocyte count is low in human NEC. We previously found that NF-κB mediates the intestinal injury in experimental NEC. However, the role of NF-κB in myeloid cells during NEC remains unclear. Herein, inhibitor of kappaB kinase β (IKKβ), a critical kinase mediating NF-κB activation, was deleted in lysozyme M (Lysm)-expressing cells, which were found to be Cd11b <superscript>+</superscript> Ly6c <superscript>+</superscript> monocytes but not Cd11b <superscript>+</superscript> Ly6c <superscript>-</superscript> macrophages in the dam-fed neonatal mouse intestine. NEC induced differentiation of monocytes into intestinal macrophages and up-regulation of monocyte recruitment genes (eg, L-selectin) in the macrophage compartment in wild-type mice, but not in pups with IKKβ deletion in Lysm <superscript>+</superscript> cells. Thus, NF-κB is required for NEC-induced monocyte activation, recruitment, and differentiation in neonatal intestines. Furthermore, pups with Lysm-IKKβ deletion had improved survival and decreased incidence of severe NEC compared with littermate controls. Decreased NEC severity was not associated with an improved intestinal barrier. In contrast, NEC was unabated in mice with IKKβ deletion in intestinal epithelial cells. Together, these data suggest that recruitment of Ly6c <superscript>+</superscript> monocytes into the intestine, NF-κB activation in these cells, and differentiation of Ly6c <superscript>+</superscript> monocytes into macrophages are critical cellular and molecular events in NEC development to promote disease.<br /> (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Antigens, Ly genetics
Enterocolitis, Necrotizing genetics
Enterocolitis, Necrotizing pathology
Epithelial Cells pathology
Gene Deletion
I-kappa B Kinase genetics
I-kappa B Kinase metabolism
L-Selectin genetics
L-Selectin metabolism
Macrophages pathology
Mice
Mice, Transgenic
NF-kappa B antagonists & inhibitors
NF-kappa B genetics
Up-Regulation
Antigens, Ly metabolism
Enterocolitis, Necrotizing metabolism
Epithelial Cells metabolism
Macrophages metabolism
Monocytes metabolism
NF-kappa B metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1525-2191
- Volume :
- 189
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The American journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 30593820
- Full Text :
- https://doi.org/10.1016/j.ajpath.2018.11.015