Neuroimmunology: A Dialogue Between Two Crucial Systems

Andrew Prevatte Neuroimmunology: A Dialogue Between Two Crucial Systems

The human body constantly collects information about its environment, sending signals, and commanding actions through an intricate network known as the nervous system. A flaw or short-circuit in the nervous system could mean catastrophe for the rest of the body. The vital importance of such a widespread system is what piqued Dr. Celia Shiau’s interest, which led her to study another crucial body system and eventually, one of the most versatile and extensive cell types in the body. Dr. Shiau works within the dynamic field of neuroimmunology, a subfield of molecular biology which examines the interaction between the nervous system and immune system, the body’s defense against infection. These two networks are often intertwined; when the nervous system is disrupted by disease, the immune system usually responds in defense. Knowing how these two systems interact can lead to a better understanding of how homeostasis, or bodily equilibrium, is maintained across the body. One particular component of the immune system is of interest to Dr. Shiau: macrophages. Macrophages, which are big “cell eaters” that help clean up cellular debris across the body, are involved in signaling and have been implicated as impacting the connections between neurons. Dr. Shiau’s states, macrophages are a “very unique and phenomenal cell type that is versatile and dynamic.” 1 Fully understanding the inner workings of macrophages would allow for major developments in immunotherapy, with widespread applications, including cancer remission. Macrophages reside in every tissue across the body, performing a myriad of different functions. In fact, they can change morphology and behavior in

Dr. Celia Shiau

response to a small change in their microenvironment. The unique sensitivity makes macrophages well-equipped for their environment in the brain, the hub of the nervous system. Macrophages that reside in the brain are known as “microglia.” Dr. Shiau specifically examines microglia, due to their unique nature of being the only type of immune cell residing in the brain. 1 Much is still unknown about microglia, but Dr. Shiau’s lab is determined to develop a better picture. What are the molecular controls that regulate activity of microglia? What genes are involved in the development of microglia, or the lack of them? What does a loss of microglia look like — are there structural changes in the brain, or consequential impacts on animal behavior? These are the questions about microglia which currently interest Dr. Shiau.

Figre 1, left: Macrophage of a mouse phagocytosing Figure 2, right: Microglia (green) and neurons. Images courtesy of Wikimedia.

In order to observe and test macrophages, Dr. Shiau uses an interesting organism, the zebrafish. Zebrafish processes bear remarkable similarities to human processes, as their tissues, organs, and cell types are highly conserved from fish to human. However, it is not only the applicability of results that drew Dr. Shiau to study this model organism. Zebrafish also have high optical transparency, meaning that the inner workings of their tissues

Figure 3: Comparison of gut microbiota with and without macrophages/ Image courtesy of Dr. Celia Shiua.

and cells are easily observed in real time. Dr. Shiau believes that observing cells in vivo, or live cells in their natural environments, is crucial to wholly understanding a process. 1 Dr. Shiau developed a novel process for time-lapse imaging during her PhD, using slices of chicken embryo brains to observe the early stages of nervous system development. 2 She brought this same level of meticulous detail to the observation of macrophages in zebrafish. Dr. Shiau has already identified multiple genes vital to macrophages, using a method known as “forward genetics.” The process of forward genetics involves making many random mutations across a genome, and then selectively isolating specific ones. Making a mutation in a gene effectively weakens or silences its expression, allowing the researcher to observe the effect (or lack thereof) of a specific gene. 1 With this method, Dr. Shiau has characterized three separate genes acting upon microglia so far: nlrc3-like, xpr1b, and irf8. 3, 4, 5 When these genes are inactivated, effects range from broad impacts on the entire macrophage population to the lack of microglia formation. For example, irf8 acts upon the DNA itself to induce precursor cells to become macrophages; without irf8, the presence of macrophages in general is in jeopardy. 5 In this same vein, Dr. Shiau has also examined the impact of a lack of macrophages in organs. In her most recent study, Dr. Shiau observed the effect of no macrophages on the gut microbiota. The gut encompasses the largest part of the nervous system, other than the brain and the spinal cord. A disruption in its population of microbes could be disastrous. While there is robust research on environmental factors affecting gut microbiota, not much is known about contribution from the host. Using zebrafish, Dr. Shiau mutated irf8, which caused no macrophages to form in the gut. As such, the gut microbiota was disrupted, and the immune system as a whole was dysregulated. 6 The research not only elucidated interesting connections between the immune system and colonization of normal gut microbes, but it also has implications for a greater understanding of the brain-gut axis. Dr. Shiau’s work is at the forefront of understanding macrophages, a unique and extensive cell type. A full picture of macrophages mechanisms will contribute to leaps in development of immunotherapy. Macrophages recognize and phagocytose, or eat, specific cells. If their fundamental engineering is understood, then we could develop treatments to remove unhealthy or cancerous cells from a patient’s body. 1 Dr. Shiau leads the charge in this unprecedented and promising field of study.

References

1. Interview with Celia Shiau, Ph.D. 2/5/20. 2. Shiau CE, Das RM, Storey KG. An effective assay for high cellular resolution time-lapse imaging of sensory placode formation and morphogenesis. BMC Neurosci. 2011, 12:37. Published 2011 May 9. doi:10.1186/1471- 2202-12-37 3. Shiau CE, Monk KR, Joo W, Talbot WS. An antiinflammatory NOD-like receptor is required for microglia development. Cell Rep. 2013, ;5(5):1342–1352. doi:10.1016/j.celrep.2013.11.004 4. Meireles AM, Shiau CE, Guenther CA, Sidik H, Kingsley DM, Talbot WS. The phosphate exporter xpr1b is required for differentiation of tissue-resident macrophages. Cell Rep. 2014, ;8(6):1659–1667. doi:10.1016/j.celrep.2014.08.018 5. Shiau CE, Kaufman Z, Meireles AM, Talbot WS. Differential requirement for irf8 in formation of embryonic and adult macrophages in zebrafish. PLoS One. 2015, ;10(1):e0117513. Published 2015 Jan 23. doi:10.1371/journal.pone.0117513 6. Earley AM, Graves CL, Shiau CE. Critical Role for a Subset of Intestinal Macrophages in Shaping Gut Microbiota in Adult Zebrafish. Cell Rep. 2018, ;25(2):424–436. doi:10.1016/j.celrep.2018.09.025