Maternal Immune Activation Blunts Proper IL-6 Mediated Brain Microglia Inflammation Response

Houston, we have a complex problem with vaccinating during pregnancy, especially early pregnancy.

Microglial play multiple roles in brain function, including aiding synapse formation and pruning as well as shifting into an autophagy mode where they can work to clean up debris from cellular injury and normal cell death. They reduce the inflammation (they control the inflammasome). Studies show when they are not available during development, the neurodevelopmental program is heavily altered. Microglia become directly activated by IL-6 in the serum; aluminum increases IL-6 activation.

Vaccination with aluminum-containing vaccines during pregnancy and early childhood must end.

From Hayes et al. (Sept 2022):

“Here we show that, after maternal immune activation (MIA) in mice, microglia from the offspring have a long-lived decrease in immune reactivity (blunting) across the developmental trajectory.”

“(Maternal Immune Activation) does not induce a distinct subpopulation but, rather, decreases the contribution to inflammatory microglia states. Prenatal replacement of microglia from MIA offspring with physiological infiltration of naive microglia ameliorated the immune blunting and restored a decrease in presynaptic vesicle release probability onto dopamine receptor type-two medium spiny neurons, indicating that aberrantly formed microglia due to an adverse prenatal environment affect the long-term microglia reactivity and proper striatal circuit development.”

Study: Hayes LN, An K, Carloni E, Li F, Vincent E, Trippaers C, Paranjpe M, Dölen G, Goff LA, Ramos A, Kano SI, Sawa A. Prenatal immune stress blunts microglia reactivity, impairing neurocircuitry. Nature. 2022 Oct;610(7931):327-334. doi: 10.1038/s41586-022-05274-z. Epub 2022 Sep 28. PMID: 36171283.

Full Abstract

“Recent studies suggested that microglia, the primary brain immune cells, can affect circuit connectivity and neuronal function1,2. Microglia infiltrate the neuroepithelium early in embryonic development and are maintained in the brain throughout adulthood3,4. Several maternal environmental factors—such as an aberrant microbiome, immune activation and poor nutrition—can influence prenatal brain development5,6. Nevertheless, it is unknown how changes in the prenatal environment instruct the developmental trajectory of infiltrating microglia, which in turn affect brain development and function. Here we show that, after maternal immune activation (MIA) in mice, microglia from the offspring have a long-lived decrease in immune reactivity (blunting) across the developmental trajectory. The blunted immune response was accompanied by changes in chromatin accessibility and reduced transcription factor occupancy of the open chromatin. Single-cell RNA-sequencing analysis revealed that MIA does not induce a distinct subpopulation but, rather, decreases the contribution to inflammatory microglia states. Prenatal replacement of microglia from MIA offspring with physiological infiltration of naive microglia ameliorated the immune blunting and restored a decrease in presynaptic vesicle release probability onto dopamine receptor type-two medium spiny neurons, indicating that aberrantly formed microglia due to an adverse prenatal environment affect the long-term microglia reactivity and proper striatal circuit development.”

“Maternal immune activation induces sustained changes in fetal microglia motility”

“MIA, particularly when induced earlier (at E12), caused sustained alterations in the patterns of microglial process motility and behavioral deficits.”

Full Abstract:

“Maternal infection or inflammation causes abnormalities in brain development associated with subsequent cognitive impairment and in an increased susceptibility to schizophrenia and autism spectrum disorders. Maternal immune activation (MIA) and increases in serum cytokine levels mediates this association via effects on the fetal brain, and microglia can respond to maternal immune status, but consensus on how microglia may respond is lacking and no-one has yet examined if microglial process motility is impaired. In this study we investigated how MIA induced at two different gestational ages affected microglial properties at different developmental stages. Immune activation in mid-pregnancy increased IL-6 expression in embryonic microglia, but failed to cause any marked changes in morphology either at E18 or postnatally. In contrast MIA, particularly when induced earlier (at E12), caused sustained alterations in the patterns of microglial process motility and behavioral deficits. Our research has identified an important microglial property that is altered by MIA and which may contribute to the underlying pathophysiological mechanisms linking maternal immune status to subsequent risks for cognitive disease.”

Study: Ozaki K, Kato D, Ikegami A, Hashimoto A, Sugio S, Guo Z, Shibushita M, Tatematsu T, Haruwaka K, Moorhouse AJ, Yamada H, Wake H. Maternal immune activation induces sustained changes in fetal microglia motility. Sci Rep. 2020 Dec 7;10(1):21378. doi: 10.1038/s41598-020-78294-2. PMID: 33288794; PMCID: PMC7721716.

Here’s a resource on the role of microglia in the brain’s immune response:

“…microglia orchestrate the brain inflammatory response, responding to CNS damage and regulating the release of soluble inflammatory mediators as well as phagocytosing CNS-specific debris [87]. Mounting evidence indicates that autophagy finely regulates both innate and adaptive responses in the peripheral immune system [16], actively influencing the outcome of inflammatory responses [88], phagocytosis [89], and antigen presentation [90]. Of note, both immune senescence [91] and the low-grade chronic inflammation that characterizes aging [92] have been correlated with impaired autophagy flux in macrophages [93]. However, few studies have evaluated the role that autophagy may play on microglia and the possible impact of autophagy dysregulation on the physiology and survival of these brain-resident macrophages. In the next sections, we will review the studies that have assessed the role of autophagy in microglial phagocytosis and inflammation and try to open new research fields based on data coming from studies mainly performed in peripheral macrophages and microglia.”

Review: Plaza-Zabala A, Sierra-Torre V, Sierra A. Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging. Int J Mol Sci. 2017 Mar 9;18(3):598. doi: 10.3390/ijms18030598. PMID: 28282924; PMCID: PMC5372614.