Innate immunity at the crossroads of healthy brain maturation and neurodevelopmental disorders

Abstract

The immune and nervous systems have unique developmental trajectories that individually build intricate networks of cells with highly specialized functions. These two systems have extensive mechanistic overlap and frequently coordinate to accomplish the proper growth and maturation of an organism. Brain resident innate immune cells - microglia - have the capacity to sculpt neural circuitry and coordinate copious and diverse neurodevelopmental processes. Moreover, many immune cells and immune-related signalling molecules are found in the developing nervous system and contribute to healthy neurodevelopment. In particular, many components of the innate immune system, including Toll-like receptors, cytokines, inflammasomes and phagocytic signals, are critical contributors to healthy brain development. Accordingly, dysfunction in innate immune signalling pathways has been functionally linked to many neurodevelopmental disorders, including autism and schizophrenia. This review discusses the essential roles of microglia and innate immune signalling in the assembly and maintenance of a properly functioning nervous system.

Figure 1.. Microglia influence a number of neurodevelopmental processes.

Population control: microglia phagocytose immature neurons in proliferative regions, directly promote cell death (via release of reactive oxygen species (ROS) and NGF), and support cell survival (via secreting pro-survival molecules such as growth factors and cytokines). Neurite maturation: microglia promote synaptogenesis, influence neurite outgrowth, and regulate axon tract fasciculation through released factors. Glial differentiation and myelination: microglial secreted factors support oligodendrocyte and astrocyte differentiation and microglia can influence myelination. Angiogenesis: microglia associate with vasculature and influence angiogenesis via yet to be determined secreted factors. Influence on NPC pool: microglia influence the size of the neural progenitor pool by secreting factors that promote NPC proliferation and by directly phagocytosing live and dead NPCs. Nitric oxide-releasing microglia can promote the switch from neurogenesis to astrogliogenesis, thereby influencing the ratio of neurons to glia. Synaptic pruning: microglia recognize and eliminate inactive synapses. Phosphatidylserine (PS) and complement components tag unnecessary synapses and act as “eat me” signals when recognized by microglia phagocytic receptors. Active synapses are protected by CD47 which, when recognized by SIRPα on microglia, acts as a “don’t eat me” signal.

Figure 2:. Inflammasome signaling contributes to cell death and neuronal morphology.

Binding of AIM2 to cytosolic DNA initiates assembly of AIM2, caspase-1, and ASC to form the inflammasome multiprotein complex. Inflammasome activation cleaves gasdermin D, of which the N-terminal fragments assemble to generate pores in the membrane to promote cytokine release and pyroptosis. Activation of the inflammasome also cleaves pro-cytokines IL-1β and IL-18 to generate active forms which can be released from the cell; however, cytokine signaling does not appear to be involved in neurodevelopmental removal of genetically compromised cells.

Figure 3:. Phagocytic signaling underlies synaptic pruning.

IL-33-ST2 signaling promotes synapse engulfment in the spinal cord and thalamus. Complement proteins (C1q, C4, and C3) are thought to mark synapses for elimination in the LGN. Astrocytes can release TGF-β to upregulate C1q on neurons. Recognition of C1q by MEGF10 is associated with astrocyte synapse elimination while CR3 recognition of C3 is associated with microglia synapse phagocytosis. Complement-mediated synapse elimination can be limited by SRPX2 binding of C1q. C1q-tagged synapses are also associated with caspase-3 and increased extracellular phosphatidylserine (PS). The phagocytic receptors TREM2, GPR56, and MERTK are thought to recognize extracellular PS and promote synapse elimination.

Figure 4:. Maternal immune activation promotes abnormal brain development and autistic-like behaviors.

Induced inflammation during pregnancy promotes inflammatory signaling that can influence embryonic development. Many factors including the maternal microbiome, T_H17 subset, baseline immunogenicity, genetic factors, and cytokine response may impact the susceptibility of the pregnancy to downstream offspring neurodevelopmental defects. Inflammatory mediators at the maternal-fetal interface may impact brain maturation through diverse mechanisms; including altered brain immune signaling, abnormalities in microglia, and cortical malformations that contribute to an altered balance of excitatory to inhibitory neurons (E/I). MIA offspring display autistic-like behaviors characterized by abnormal communication, stereotyped/repetitive actions, and impaired sociability.