Maternal Innate Immune Activation by Poly(I:C) Induces the Expression of the Cytokines IL-1ƒ" and IL-13, Chemokine MCP-1, and Colony Stimulating Factor VEGF in Fetal Mouse Brain

Background: Maternal viral infection during pregnancy is associated with an increase in the incidence of psychiatric disorders with neuro-developmental origin including autism spectrum disorders, intellectual and developmental disabilities, and schizophrenia.  The enhanced risk for developing mental illness is not associated with a direct injury to the central nervous system (CNS) by the infecting agent (virus or bacteria), but rather it appears to be caused by the effects of innate immune response secreted factors (IRSF) on the developing brain.  IRSF released during the activation of an innate immune response, (cytokines, chemokines, and colony stimulating factors (CSF)), modulate various aspects of neural development including neuronal survival, differentiation, and growth.  Increased cytokines levels are observed in neurodegenerative disorders and in depression, suggesting that abnormal activation of IRSF-mediated signaling in the CNS affects brain development and causes permanent changes that increase the risk for developing psychopathology in childhood and adolescence.  However, evidence for a direct association between the effect of a particular IRSF on brain development and the appearance of behavioral abnormalities has only recently started to be investigated.

Objectives: To identify the soluble factors expressed in the developing brain, this study examined the effect of innate immune response activation by a synthetic analogue of viral double-stranded RNA on the expression levels of pro and anti-inflammatory cytokines, chemokines, and colony stimulating factors in fetal and postnatal mouse brain 6h and 24h after immune response activation.

Methods: C57BL/6J pregnant mice (gestational day (GD) 16) or newborn mice (postnatal day (PND) 4) received a single intraperitoneal injection of the synthetic analogue of viral double-stranded RNA polyriboinosinic-polyribocytidilic acid (poly I:C) [20 mg/kg].  Thirty-two immune response-associated soluble factors (IRSF) including pro and anti-inflammatory cytokines, and chemokines, colony stimulating factors were assayed 6h and 24h after the injection using multiplexed bead-based immunoassay (Milliplex^TM Map) and processed in a Luminex 100 ^TM IS instrument.

Results:  Maternal exposure to poly(I:C) at GD16 induced a significant increase in cytokines IL-1beta, IL-7, and IL-13; chemokines MCP-1, MIP-1alpha, IP-10, and MIG; and in the colony stimulating factor VEGF in the fetal brain.  IL-1beta showed the highest concentration levels in the fetal brain and was the only cytokine significantly up-regulated 24h after maternal poly(I:C) injection, suggesting that IL-1beta may have a prominent impact on CNS development. These changes in IRSF levels observed in the fetal brain did not correlate with IRSF concentration levels on the maternal serum.  In contrast, poly(I:C) treatment in PND 4 pups induced a pronounced rise in chemokines and colony stimulating factors in their brains instead of the pro-inflammatory cytokine IL-1beta.

Conclusions:  This study identified the cytokines IL-1beta, IL-13, the chemokines MCP-1, and the CSF VEGF significantly increased in the developing CNS following the activation of an innate immune response, suggesting that these factors can impinge on CNS development during activation of the innate immune response and have potential long-lasting consequence on animal behavior.  Future studies will focused on the effect of these IRSF on animal behavior.