Matrix metalloproteinase-3 is a possible mediator of neurodevelopmental impairment due to polyI:C-induced innate immune activation of astrocytes

Abstract

Increasing epidemiological evidence indicates that prenatal infection and childhood central nervous system infection with various viral pathogens enhance the risk for several neuropsychiatric disorders. Polyriboinosinic-polyribocytidilic acid (polyI:C) is known to induce strong innate immune responses that mimic immune activation by viral infections. Our previous findings suggested that activation of the innate immune system in astrocytes results in impairments of neurite outgrowth and spine formation, which lead to behavioral abnormalities in adulthood. To identify candidates of astrocyte-derived humoral factors that affect neuronal development, we analyzed astrocyte-conditioned medium (ACM) from murine astrocyte cultures treated with polyI:C (polyI:C-ACM) by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Through a quantitative proteomic screen, we found that 13 protein spots were differentially expressed compared with ACM from vehicle-treated astrocytes (control-ACM), and characterized one of the candidates, matrix metalloproteinase-3 (Mmp3). PolyI:C treatment significantly increased the expression levels of Mmp3 mRNA and protein in astrocytes, but not microglia. PolyI:C-ACM was associated with significantly higher Mmp3 protein level and enzyme activity than control-ACM. The addition of recombinant Mmp3 into culture media impaired dendritic elongation of primary cultured hippocampal neurons, while the deleterious effect of polyI:C-ACM on neurite elongation was attenuated by knockdown of Mmp3 in astrocytes. These results suggest that Mmp3 is a possible mediator of polyI:C-ACM-induced neurodevelopmental impairment.

Astroglial major histocompatibility complex class I following immune activation leads to behavioral and neuropathological changes

“…Oxidative stress may be a common pathological mechanism leading to the impairment of PV (+) GABAergic interneurons (Steullet et al, ). We should investigate in future whether neuropathological changes such as microglial activation in sH‐2D‐expressing mice are mainly related to MHCI or another molecule expressed and released by astrocytes (Liddelow et al, ; Steullet et al, ; Yamada et al, ). Further studies are needed to clarify that the behavioral and neuropathological changes in sH‐2D‐expressing mice are associated with astrocyte‐derived exosomes.…”

Induction of interferon-induced transmembrane protein 3 gene expression by lipopolysaccharide in astrocytes

“…Astrocyte culture was performed as described previously (Ibi et al, 2013;Yamada et al, 2014). Briefly, astrocytes were isolated from the cortices and hippocampi of the postnatal (day 0-2) ICR mice.…”

Therapeutic Targets for Neurodevelopmental Disorders Emerging from Animal Models with Perinatal Immune Activation

“…Meanwhile, astrocytes also coordinate immune response to invading pathogens and peripheral inflammatory factors [ 60 ]. In fact, it has been reported that thousands of molecules are released from astrocytes responding to pro- and anti-inflammatory cytokines and TLR ligands such as bacterial LPS and specific nucleic acids like polyI:C [ 40 , 61 , 62 , 63 , 64 , 65 ]. Astrocytes exposed with maternally derived cytokines after MIA seem to secrete various cytokines that affect brain development.…”

“…Astrocytes exposed with maternally derived cytokines after MIA seem to secrete various cytokines that affect brain development. Regarding TLRs expressed in astrocytes, it is noteworthy that TLR 3 is the predominant one [ 40 , 63 , 64 ], given that the basal expression levels of TLR 3 in neurons and microglia are even lower than in astrocytes [ 40 , 63 ]. PolyI:C and viral nucleic acids supposedly target the TLR 3 of astrocytes in either the brain or the BBB.…”

“…PolyI:C and viral nucleic acids supposedly target the TLR 3 of astrocytes in either the brain or the BBB. We have previously demonstrated that the humoral factors released from astrocytes stimulated with polyI:C disrupt neuron–glia interactions, resulting in neurodevelopment impairment [ 40 , 63 ]. In addition, CNS infection by the protozoan parasite toxoplasma gondii is suggested to affect brain development and function though the humoral factors released from astrocytes [ 15 , 66 ].…”