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

NF-kappaB binding sites are present in the promoter regions of many acute p hase and inflammatory response genes, suggesting that NF-kappaB plays an im portant role in the initiation of innate immune responses. However, targete d mutations of the various NF-kappaB family members have yet to identify me mbers responsible for this critical role. ReIA-deficient mice die on embryo nic day 15 from TNF-alpha -induced liver degeneration. To investigate the i mportance of ReIA in innate immunity, we genetically suppressed this embryo nic lethality by breeding the ReIA deficiency onto a TNFR type 1 (TNFR1)-de ficient background. TNFR1/RcIA-deficient mice were born healthy, but were s usceptible to bacterial infections and bacteremia and died within a few wee ks after birth. Hemopoiesis was intact in TNFR1/RelA-deficient newborns, bu t neutrophil emigration to alveoli during LPS-induced pneumonia was severel y reduced relative to that in wild-type or TNFR1-deficient mice. In contras t, radiation chimeras reconstituted with ReIA or TNFR1/ReIA-deficient hemop oietic cells were healthy and demonstrated no defect in neutrophil emigrati on during LPS-induced pneumonia. Analysis of RNA harvested from the lungs o f mice 4 h after LPS insufflation revealed that the induction of several ge nes important for neutrophil recruitment to the lung was significantly redu ced in TNFR1/ReIA-deficient mice relative to that in wild-type or TNFR1-def icient mice. These results suggest that TNFR1-independent activation of ReI A is essential in cells of nonhemopoietic origin during the initiation of a n innate immune response.