Maternal Type-I interferon signaling adversely affects the microglia and the behavior of the offspring accompanied by increased sensitivity to stress

Abstract

Viral infection during pregnancy is often associated with neuropsychiatric conditions. In mice, exposure of pregnant dams to the viral mimetic poly(I:C), serves as a model that simulates such pathology in the offspring, through a process known as Maternal Immune Activation (MIA). To investigate the mechanism of such effect, we hypothesized that maternal upregulation of Type-I interferon (IFN-I), as part of the dam's antiviral response, might contribute to the damage imposed on the offspring. Using mRNA sequencing and flow cytometry analyses we found that poly(I:C) treatment during pregnancy caused reduced expression of genes related to proliferation and cell cycle in the offspring's microglia relative to controls. This was found to be associated with an IFN-I signature in the embryonic yolk sac, the origin of microglia in development. Neutralizing IFN-I signaling in dams attenuated the effect of MIA on the newborn's microglia, while systemic maternal administration of IFNβ was sufficient to mimic the effect of poly(I:C), and led to increased vulnerability of offspring's microglia to subsequent stress. Furthermore, maternal elevation of IFNβ resulted in behavioral manifestations reminiscent of neuropsychiatric disorders. In addition, by adopting a "two-hit" experimental paradigm, we show a higher sensitivity of the offspring to postnatal stress subsequent to the maternal IFNβ elevation, demonstrated by behavioral irregularities. Our results suggest that maternal upregulation of IFN-I, in response to MIA, interferes with the offspring's programmed microglial developmental cascade, increases their susceptibility to postnatal stress, and leads to behavioral abnormalities.

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

“…In contrast, the intracerebroventricular injection of rIFN-β increased the pro-inflammatory state of microglia cells and complement-dependent synapse elimination in the CNS of a mouse AD model, while blocking the type-I IFN receptor IFNAR1 diminished these effects [209]. The number of IBA1-, CD45-and CD68-positive microglia was also increased following the IFN-β treatment of GBM8-fluc-implanted athymic nude mice [210] and in the offspring of IFN-β-treated mice [211]. In line with these results, the microglial surface expression of the inflammation-associated Fc receptor and major histocompatibility complex class II (MHC-II) proteins was increased following the in vitro administration of IFN-β [212].…”

“…The levels of CCL5 and CCL2, two major chemo-attractants of peripheral immune cells, were increased in MG6-1 microglia cells, cultured in the presence of IFN-β and TNFα [ 215 ], and in IFN-β-treated primary mouse microglia cultures [ 202 ]. Moreover, IFN-β and IFN-α enhanced the expression levels of TNF, IL-6, IL-1β, IL-1α, CXCL10, CXCL9 and NO in (LPS-stimulated) primary rodent microglia cultures [ 209 , 212 , 213 , 216 , 217 , 218 ] and microglia isolated after the maternal separation of the offspring of immune-activated dams [ 211 ]. Furthermore, the two interferons downregulated the levels of superoxide anions and glutamate [ 216 ], both related to neurotoxicity, and the IFN-β treatment of the primary cultures of microglia stimulated with DNA or RNA upregulated the expression of the members of the Pyrin and HIN200 domain-containing proteins (PYHIN) family of DNA sensors [ 219 ], all again pointing to an IFN-mediated switch towards a more pro-inflammatory microglia milieu.…”

“…In cultured microglia, more than in cultured astrocytes, IFN-α upregulated a wide set of genes related to pathogen detection and elimination, as well as a pro-inflammatory M1 phenotype [ 217 , 218 ]. Furthermore, the systemic administration of IFN-β to dams of a mouse maternal immune activation model increased the stress sensitivity of fetal microglia [ 211 ], showing its profound effect on this cell type. Interestingly, neuronal and astrocyte IFNAR signaling, as well as the resulting secreted factors have been found to be important for the activation and proliferation of microglia [ 221 ].…”

Emerging Developments in Human Induced Pluripotent Stem Cell-Derived Microglia: Implications for Modelling Psychiatric Disorders With a Neurodevelopmental Origin

“…Toll-like receptor 3 (TLR3) activation or application of single cytokines such as IL-6 could for example be used to phenocopy (to some extent) MIA in vitro using a human model system. This could then be compared to data from rodent models, for example the effect on microglia transcriptional profile and chromatin state, which is known to be abnormal early in development following MIA (122,123). Such studies could be extended to examine how the inflammatory exposure might interact with specific genetic risk backgrounds, although this likely would be a complex undertaking.…”

Fetal innate immunity contributes to the induction of atypical behaviors in a mouse model of maternal immune activation

“…Interestingly, a few reports have suggested that MIA alters gene expression in fetal microglia (Ben-Yehuda et al, 2020;Matcovitch-Natan et al, 2016;Mattei et al, 2017).…”