Maternal Immune Activation Leads to Activated Inflammatory Macrophages in Offspring

Background:  Several epidemiological studies have shown an association between infection or inflammation during pregnancy and increased risk of autism in the child.  In addition, animal models have illustrated that maternal inflammation during gestation can cause autism-relevant behaviors in the offspring; so called maternal immune activation (MIA) models. More recently, changes in T cell cytokine responses were reported in children with autism and in offspring of MIA mice; however, the cytokine responses of other immune cell populations have not been thoroughly investigated in these MIA models.

Objectives:  Similar to changes in T cell function, we hypothesized that following MIA, offspring will have long-term changes in macrophage function.

Methods:  To test this theory, we utilized the polyinosinic-polycytidylic acid [poly(I:C)] MIA mouse model in C57BL/6J mice and examined macrophage cytokine production in adult offspring. Pregnant dams were given either a single injection of 20 mg/kg poly(I:C), or saline delivered intraperitoneally on gestational day 12.5.  When offspring of poly (I:C) treated dams reached 10 weeks of age, femurs were collected and bone marrow-derived macrophages were generated. Cytokine production was measured in bone marrow-derived macrophages incubated for 24 hours in either growth media alone, LPS, IL-4/ LPS, or IFN-γ/ LPS.

Results:  Following stimulation with LPS alone, or the combination of IFN-γ/LPS, macrophages from offspring of poly (I:C) treated dams produced higher levels of IL-12(p40) (p < 0.04) suggesting an increased M1 polarization.  In addition, even without the presence of a polarizing cytokine or LPS stimulus, macrophages from offspring of poly (I:C) treated dams exhibited a higher production of CCL3 (p = 0.05).  Moreover, CCL3 levels were further increased when stimulated with LPS, or polarized with either IL-4/LPS or IFN-γ/LPS (p < 0.05) suggesting a general increase in production of this chemokine.

Conclusions:  Collectively, these data suggest that MIA can produce lasting changes in macrophage function that are sustained into adulthood.