Targeted mutation of TNF receptor I rescues the ReIA-deficient mouse and reveals a critical role for NF-κB in leukocyte recruitment

NF-kappaB binding sites are present in the promoter regions of many acute phase and inflammatory response genes, suggesting that NF-kappaB plays an important role in the initiation of innate immune responses. However, targeted mutations of the various NF-kappaB family members have yet to identify members responsible for this critical role. ReIA-deficient mice die on embryonic day 15 from TNF-alpha -induced liver degeneration. To investigate the importance of ReIA in innate immunity, we genetically suppressed this embryonic lethality by breeding the ReIA deficiency onto a TNFR type 1 (TNFR1)-deficient background. TNFR1/RcIA-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 ReIA or TNFR1/ReIA-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/ReIA-deficient mice relative to that in wild-type or TNFR1-deficient mice. These results suggest that TNFR1-independent activation of ReIA is essential in cells of nonhemopoietic origin during the initiation of an innate immune response.