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Targeted Mutation of TNF Receptor I Rescues the RelA-Deficient Mouse and Reveals a Critical Role for NF-κB in Leukocyte Recruitment

Alcamo, Elizabeth and Mizgerd, Joseph P. and Horwitz, Bruce H. and Bronson, Rod and Beg, Amer A. and Scott, Martin and Doerschuk, Claire M. and Hynes, Richard O. and Baltimore, David (2001) Targeted Mutation of TNF Receptor I Rescues the RelA-Deficient Mouse and Reveals a Critical Role for NF-κB in Leukocyte Recruitment. Journal of Immunology, 167 (3). pp. 1592-1600. ISSN 0022-1767. doi:10.4049/jimmunol.167.3.1592.

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NF-κB binding sites are present in the promoter regions of many acute phase and inflammatory response genes, suggesting that NF-κB plays an important role in the initiation of innate immune responses. However, targeted mutations of the various NF-κB family members have yet to identify members responsible for this critical role. RelA-deficient mice die on embryonic day 15 from TNF-α-induced liver degeneration. To investigate the importance of RelA in innate immunity, we genetically suppressed this embryonic lethality by breeding the RelA deficiency onto a TNFR type 1 (TNFR1)-deficient background. TNFR1/RelA-deficient mice were born healthy, but were susceptible to bacterial infections and bacteremia and died within a few weeks after birth. Hemopoiesis was intact in TNFR1/RelA-deficient newborns, but neutrophil emigration to alveoli during LPS-induced pneumonia was severely reduced relative to that in wild-type or TNFR1-deficient mice. In contrast, radiation chimeras reconstituted with RelA or TNFR1/RelA-deficient hemopoietic cells were healthy and demonstrated no defect in neutrophil emigration during LPS-induced pneumonia. Analysis of RNA harvested from the lungs of mice 4 h after LPS insufflation revealed that the induction of several genes important for neutrophil recruitment to the lung was significantly reduced in TNFR1/RelA-deficient mice relative to that in wild-type or TNFR1-deficient mice. These results suggest that TNFR1-independent activation of RelA is essential in cells of nonhemopoietic origin during the initiation of an innate immune response.

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Baltimore, David0000-0001-8723-8190
Additional Information:© 2001 by The American Association of Immunologists. Received for publication December 12, 2000. Accepted for publication May 17, 2001. We thank Carlos Lois, Kairbaan Hodivala-Dilke, and Stephen Robinson for helpful suggestions and critical review of this work. This work was supported by the National Institutes of Health grants (to D.B., E.A., B.H.H., and M.S.). J.P.M. was supported by a research grant from the American Lung Association and a Parker B. Francis Fellowship from the Francis Families Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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American Lung AssociationUNSPECIFIED
Francis Families FoundationUNSPECIFIED
Issue or Number:3
Record Number:CaltechAUTHORS:20200506-102014044
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Official Citation:Targeted Mutation of TNF Receptor I Rescues the RelA-Deficient Mouse and Reveals a Critical Role for NF-κB in Leukocyte Recruitment. Elizabeth Alcamo, Joseph P. Mizgerd, Bruce H. Horwitz, Rod Bronson, Amer A. Beg, Martin Scott, Claire M. Doerschuk, Richard O. Hynes, David Baltimore. The Journal of Immunology August 1, 2001, 167 (3) 1592-1600; DOI: 10.4049/jimmunol.167.3.1592
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103026
Deposited By: Tony Diaz
Deposited On:06 May 2020 17:55
Last Modified:16 Nov 2021 18:17

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