The adaptation of microglia (brain macrophages) to brain development

Microglia is a brain-specific macrophage lineage that seeds the developing brain tissue in utero (embryonic) and contributes to "patterning and wiring of the brain in early development and contribute to homeostasis throughout life". Since brain is cocooned from the rest of the body by blood-brain barrier (BBB), it is not clear whether microglia, as a member of innate immune system, is responsive to signals generated within immune system.

New study in Science suggests that brain resident microglia undergo time-dependent step-wise upgrades and retains sensitivities to signals derived from immune system and microbiota.

Basically for this study the authors analyzed gene expression profile of microglia (both from single cell and from the pool) harvested from brain at different developmental stage (in utero (embryonic), newborn and adult).      

Interestingly and relevant for medicine, the authors could show that systemic activation of immune system by poly I:C could disrupt normal formation of newborn microglia by switching its developmental program to more adult microglia-like setting. 

Such changes in newborn microglia can potentially underlie neuro-developmental challenges in babies born to mothers experiencing immune activation (viral infections) during pregnancy.   

David Usharauli

TNF-α sensing by brain is required for early mobilization of adaptive immune system

Very few studies have been done with the focus on understanding the relationship between brain and adaptive immune system. In principle, rapid sensing of peripheral insults by neurons and information analysis by brain could facilitate efficient recruitment of adaptive immune cells.

For example, new study in journal Nature Immunology provided evidence to suggest that infection-associated TNF-α signals brain (hypothalamus) to induce rapid lypolysis in adipose tissue and recruitment of adaptive immune cells.

Initially, the authors showed that direct injection of 10pg of TNF-α into mouse hypothalamus induced rapid mobilization of T and B cells in the spleen and adipose tissue (similar effect was seen with an intravenous L.M infection). 

Next, the authors showed that such mobilization of adaptive immune cells during an intravenous L.M infection was reduced when TNF-α antagonist was injected into hypothalamus. 

Similarly, such mobilization of adaptive immune cells in the spleen and adipose tissue during an intravenous L.M infection was reduced when TNF-α signaling was inhibited in hypothalamus by shRNA.

Conversely, when TNF-R deficient mice were injected in the hypothalamus with lentivirus construct encoding TNFR1, mobilization of adaptive immune cells in the spleen and adipose tissue was restored during an intravenous L.M infection.

Furthermore, sympathetic denervation of adipose tissue also abolished mobilization of adaptive immune cells in the spleen and adipose tissue in response to hypothalamic TNF-α injection.

Next, the authors showed that mobilization of adaptive immune cells in the spleen and adipose tissue in response to an intravenous L.M infection or hypothalamic TNF-α injection was reversed by lypolysis inhibitor, implying that brain signaled the adaptive immune system via lipid metabolites.

Finally, the authors made observation that diet-induced obesity rendered mice insensitive to hypothalamic injection of TNF-α, provided indirect evidence of diminished immune activity in obesity.

In summary, these results points to a novel inter-talk mechanism, based on lypolysis products, between brain and adaptive immune system at an early stage of infection. Right now it is not clear whether this brain-assisted rapid mobilization of adaptive immune cells could translate into efficient immune response against infection later on. 

David Usharauli