Maternal and Postnatal Effects of Poly I:C-Induced Intrauterine Inflammation and Rytvela, a Non-Competitive IL-1R...

Maternal infection-induced inflammation during pregnancy is associated with adverse neurodevelopment. Rytvela, an allosteric IL-1 receptor antagonist, reduces IL-1β-mediated pathology in fetal rodents and sheep. However, its effects on TLR3-mediated inflammation and subsequent offspring growth and behavior remain unclear. Using precocial spiny mice, the primary outcome of this study was to examine whether rytvela could attenuate the acute maternal inflammatory response to mid-gestation exposure to polyinosinic:polycytidylic acid (Poly(I:C)). Secondary offspring outcomes included postnatal growth and behavior. At gestational day 20 (term = 39 days), pregnant mice received two intraperitoneal injections, 4 h apart, of saline (0.9% w/v, n = 14), Poly(I:C) (12 mg/kg, n = 14), or Poly(I:C) + rytvela (12 mg/kg + 3 mg/kg, respectively, n = 14). Ten dams/group were culled 8 h after dose 1 to assess inflammatory responses. The remainder (n = 4 dams/group) were delivered at term. Offspring (control n = 7, Poly(I:C) n = 8, Poly(I:C) + rytvela n = 11) growth was monitored and behavioral testing undertaken from postnatal day (PND) 3-45. Poly(I:C) increased maternal serum (p = 0.01) and amniotic fluid (p = 0.003) IL-1β, and upregulated Il1b, Il6 and Tnf expression in the spleen and thymus. Rytvela reduced IL-1β levels but did not attenuate elevated cytokine gene expression. Poly(I:C) slowed postnatal growth (PND 18-27, p < 0.05), which recovered earlier with rytvela. Poly(I:C) exposure did not alter offspring behavior in tests completed to PND 45. However, Poly(I:C) + rytvela offspring showed reduced locomotor activity (distance: p < 0.001; velocity: p = 0.021). In conclusion, rytvela attenuated the primary inflammatory response to Poly(I:C), promoting earlier postnatal growth recovery despite persistent cytokine gene expression. Reduced locomotor activity after prenatal rytvela exposure warrants further investigation.