Microglia with Memory Functions Are Domesticated to Alleviate Neuropathic Diseases

Neuroinflammation is involved in the pathogenesis of almost all central nervous system diseases. As intrinsic immune cells of the brain, microglia regulate their activity according to the dynamic brain environment. Previous studies have shown that repeated peripheral inflammation can trigger long-term changes in microglia gene expression and function, a form of intrinsic immune memory.

A study has provided new insights into microglia changes in immune memory formation. Understanding these underlying mechanisms will aid in the future development of therapies to enhance or inhibit microglia activity inappropriately in the context of brain disease.

Creative Biolabs shares research ideas that support the dynamic regulation of microglia in the formation of immune memory in the brain, providing support for future utilization of the model in the context of brain disease. The table below shows the related services we provide.

Microglia are Specialized Immune Cells in the Central Nervous System

Microglia originate from monocytes and their precursors that traverse the vessel wall during the period of embryonic cerebral vasculogenesis, and become quiescent microglia in the form of tiny branching cells after neurodevelopmental maturation.

• As resident immune cells of the brain, microglia respond rapidly to inflammation and participate in classical immune functions, including cytokine and chemokine production and phagocytosis of pathogens and cellular debris.
• In addition to their responsibilities as immune cells, microglia play critical roles in maintaining brain homeostasis, including regulating the number of neurons and oligodendrocytes, shaping brain circuitry, and fine-tuning neural connections.

These processes are often disrupted in brain diseases, supporting the important role of microglia in health and disease. As intrinsic immune cells of the brain, microglia are unique in that they are long-lived cells capable of localized self-renewal throughout their lifespan, suggesting that the formation of intrinsic immune memories in microglia may have a lasting impact on brain function and disease development.

For microglia related research, we also offer a range of research tools, including but not limited to the following:

Microglial Cells Respond to Immune Memory in the Brain

Intrinsically immune cells, including microglia, express receptors that respond to microbe-associated molecular patterns. Microglial cells' Toll-like receptor 4 (TLR4) binds lipopolysaccharide (LPS), a major structural component of Gram-negative bacteria.

• Repeated low-dose peripheral injections of LPS are an effective model for studying the immune memory response of microglia in the brain.
• Repeated LPS stimulation induces long-term immune training and tolerance in brain microglial cells, a state that has been shown to persist for at least 6 months.
• One study used a mouse model of repeated LPS to identify how changes in gene expression, cytokine expression, and microglial cell morphology drive the formation of training and tolerance in the brain.

Repeated Peripheral Injections of LPS Trigger Training and Tolerance in Microglia

It has been shown that in an Alzheimer's disease model, gene expression and enhancer activity of microglia are altered 6 months after LPS injection, suggesting long-term reprogramming of microglia function after repeated LPS. In the latest study, researchers identified LPS-sensitive differentially expressed genes (DEGs) that are enriched for the interferon (IRF) family and NFkB transcription factor motifs in their promoters.

• IRF family transcription factors have been shown to be required for Il-1β expression in microglia after peripheral nerve injury and regulate disease-related microglial gene expression, including Apoe and Trem2.
• IRF8 was particularly well characterized in microglia and was shown to bind and regulate microglial enhancer regions during postnatal development to help establish microglia identity and function. Microglia deficient in IRF8 exhibit significant morphological and functional changes.
• The enriched direct binding sites for NfkB/p65 and IRF8 were found in DEGs identified in the latest study, suggesting that the coordinated activity of these transcription factors is a key regulator of immune activation and tolerance in the brain.

Microglia May Collaborate with Other Cell Types to Sustain Expression of Proinflammatory Cytokines

The effects of peripherally administered LPS may be transmitted to the brain parenchyma via TLR4 receptors on meninges and endothelial cells, which subsequently signal other cell types, including microglia. Microglia may collaborate with other cell types, such as astrocytes, to consistently express pro-inflammatory cytokines, as removal of microglia alone does not alleviate LPS-induced disease behavior.

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• Once immune signaling molecules reach the brain parenchyma, they can bind to cytokine receptors expressed on neurons and glial cells, directly or indirectly modulating neuronal firing properties, which ultimately affects circuit function and downstream behavior.
• The 4xLPS-sensitive differentially expressed gene cluster identified in the most recent study was uniquely enriched for gene ontology terms associated with astrocyte development, suggesting that astrocytes may play an important role in immune memory models.

Astrocytes exhibited LPS-induced immune training and tolerance and responded to signals from microglia after LPS exposure. Future cell type-specific experiments in the same repetitive LPS model could further distinguish the contribution of microglia from other immune cell types as well as other brain cell types in the observed differences in gene expression.

Future studies could further identify how microglia maintain innate immune memory and influence disease risk. Understanding these underlying mechanisms will aid in the future development of therapies to enhance or inhibit microglia activity inappropriately in the context of brain disease.

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