A rock in the toll road: IRAK4 inhibition of TLR4-MyD88 signaling as potential treatment for addiction

Abstract

Birth is preceded by inflammation at the fetal/maternal interface. Additionally, the newborn experiences stimuli that under any other circumstance could elicit an immune response. It is unknown, however, whether birth elicits an inflammatory response in the newborn that extends to the brain. Moreover, it is unknown whether birth mode may alter such a response. To study these questions, we first measured corticosterone and pro- and anti-inflammatory cytokines in plasma of mouse offspring at several timepoints spaced closely before and after a vaginal or Cesarean birth. We found highest levels of IL-6 one day before birth and surges in corticosterone and IL-10 just after birth, regardless of birth mode. We next examined the neuroimmune response by measuring cytokine mRNA expression and microglial number and morphology in the paraventricular nucleus of the hypothalamus and hippocampus around the time of birth. We found a marked increase in TNF-α expression in both brain regions a day after birth, and rapid increases in microglial cell number in the first three days postnatal, with subtle differences by birth mode. To test whether the association between birth and cytokine production or expansion of microglia is causal, we manipulated birth timing. Remarkably, advancing birth by a day advanced the increases in all of the markers tested. Thus, birth triggers an immune response in the body and brain of offspring. Our results may provide a mechanism for effects of birth (e.g., acute changes in cell death and neural activation) previously reported in the newborn brain.