LPS-induced murine abortions require C5 but not C3, and are prevented by upregulating expression of the CD200 tolerance signaling molecule

Problem: Lipopolysaccharide (LPS) acts via tlr4 to promote Th1 cytokine secretion and abortions. LPS is an essential co-factor in spontaneous abortion in the CBA × DBA/2 model and in stress-triggered abortions. In the CBA × DBA/2 model, C3a, C5a, and fgl2 prothrombinase participate in triggering inflammation that terminates embryo viability. As fgl2 prothrombinase (via thrombin) can generate C5a, it was predicted that LPS-driven abortions (which require fgl2) would be independent of C3. CD200Fc can prevent abortions in the CBA × DBA/2 model, but an action through Fc could not be excluded. Method od study: C3^-/- and C5^-/- knock-out mice on a B6 background were syngeneically mated and Salmonella enteritidis LPS was administered i.p. on day 6.5 or pregnancy along with 2mg progesterone in sesame oil s.c. The total number of implants and the number of resorbing embryos were counted on day 13.5 of pregnancy. CD200-rtTA double transgenic homozygous males (B6 background) mated with B6^+/+ females were similarly treated. To up-regulate CD200 expression in embryonic trophoblasts, doxycycline was added to the drinking water from the time of mating. Results: The LPS boosted the abortion rate from 15.5% (control) to 42.0% in C3^-/- mice (χ² = 9.28, P < 0.005). In C5^-/- mice, there was no increase in abortion rate with LPS compared to progesterone-treated controls (22.8% versus 26.3%, P = NS). LPS-treated transgenic mice given LPS+progesterone had a 42.5% abortion rate, but when the mice were given doxycycline to induce expression of CD200 by the embryo, the abortion rate was only 8.3% (χ² = 14.40, P < 0.005, Fisher's exact test P = 0.00007). Conclusion: C5, but not C3, appears necessary for LPS-driven abortions. Up-regulation of CD200 can prevent LPS-driven abortions, possibly by altering dendritic cells to promote Treg cell development or by a direct suppressive action on macrophages and mast cells that also express CD200 receptors.