Cytokine involvement in microglia proliferation

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Microglia are the resident immune cells of the brain and spinal cord with critical roles in their development and maintenance. Microglia proliferate in the first weeks of life to achieve a density that is maintained throughout life by cell division (proliferation), cell death, and cell-to-cell repulsion between adjacent microglia. Currently, it is unclear how this microglia density is initially achieved developmentally and sustained in adulthood. Research suggests that the IL1 cytokines may regulate microglia proliferation. As I establish my new laboratory, I will develop a long-term program to understand how microglia density is 1) initially achieved in development and 2) sustained throughout adult life. My short-term objectives are to determine if IL1 cytokines and perhaps also other factors regulate microglia proliferation in the developing and adult brain. I will use available mouse models to determine what factors promote microglia proliferation. AIM 1: Identify the IL-1 cytokines responsible for microglia proliferation during development. Microglia proliferate extensively in the first two weeks after birth. Little is known on what factor(s) is(are) responsible for driving microglia proliferation during this early postnatal period, but microglia do proliferate in response to several factors called cytokines during injury including IL1 cytokines. To answer this question, a graduate student will measure microglia proliferation in the developing brain of mice deficient for IL1 cytokines and receptors. AIM 2: Determine whether homeostatic microglia densities require IL1 cytokines in adults. How microglia density is maintained throughout life is unknown, but one possibility is that interleukin 1 cytokines promote slow ongoing proliferation. To evaluate this possibility, a graduate student will assess microglia proliferation and cell death in adult mice deficient for IL1 cytokines and receptors. This aim allows an appreciation of whether microglia require ongoing IL1 cytokines to sustain proliferation. AIM 3: Identify other factors that are necessary for microglia proliferation. In my postdoctoral work, I identified potential microglia proliferation-inducing factors. A graduate student will screen these candidate factors to identify new molecules that promote microglia proliferation. The graduate student will screen these factors with purified microglia cultures and determine their capacity to stimulate microglia proliferation in vitro. They will also assess whether these new factors promote microglia proliferation in the developing brain. This aim will identify new factors that stimulate microglia proliferation. Microglia are an essential cell to healthy brain function. Our work will be the first to identify factors that regulate their production in the developing and adult brain. The outcomes will advance our understanding of microglia production contribute to building and maintaining the brain throughout life.