Wednesday, April 24, 2024
4/24/2024
Project Summary: Stroke is the fifth leading cause of death in the United States, predominantly affecting aged people. FDA approved treatments are proving inadequate as many patients are ineligible for reperfusion therapies and they fail to treat secondary brain injury or help in brain repair. One of the most promising therapies for stroke is targeting the peripheral and central nervous system immune responses that have modulatory roles during all stages of stroke pathobiology. Aging affects immunologic responses by a global suppression of the immune system, including dysregulation of cytokine mediators, leading to increased inflammation throughout all systems, termed inflammaging. However, understanding mechanisms of healthy aging can bypass this effect. Two candidate immune cells (1) microglia, brain-resident macrophages, and (2) innate lymphoid cells, a newly discovered innate immune cell, may control pre- and post-stroke responses in the aged brain. Microglia immunosurveil the brain during homeostasis and are quickly primed once injury is detected. Unfortunately, they are affected by inflammaging causing them to be poor at anti-inflammatory responses, especially after brain injury. Group 2 innate lymphoid cells (ILC2s) are a prime candidate in regulating microglial responses as they produce anti-inflammatory cytokines (IL-4, IL-5, and IL-13) during times of injury. These cytokines modulate microglia to a reparative phenotype by increasing their trophic and phagocytic capacity through upregulation of healing proteins like heme oxygenase 1, arginase 1, and vascular endothelial growth factor alpha. The communication between macrophages and ILC2s have been investigated peripherally in kidney ischemic- reperfusion injury, but very little brain and in aging. Preliminary data show that with age, ILC2s increase in the brain of male and female mice compared to other ILC types. Moreover, males have a multi-fold global increase of total ILC and ILC2 counts putting their total ILC and ILC2 counts greater than females. Also, male ILC2s produce more cytokines and have a greater anti-inflammatory capacity in aging than females. Lastly, young ILC2 soluble factors increase Nrf2 and Nrf2-regulated genes in microglia in vitro. This would suggest that aged ILC2s could be beneficial in microglia polarization during inflammatory responses. Therefore, I hypothesize that ILC2s are the brain’s gatekeepers of microglia polarization to a reparative, M2-like phenotype under: (1) homeostatic conditions, (2) ischemic insult, and (3) with aging. In Aim 1, I will investigate the transcriptome of ILC2s and ILC2 soluble factors on microglia polarization. In Aim 2, I will identify the response of ILC2s to oxygen-glucose deprivation, an in vitro model of ischemic injury, and how their soluble factors polarize primed microglia. Lastly, in Aim 3, I will perform a “proof-of-concept” experiment to inquire the role of ex-vivo stimulated ILC2s on aged microglia via adoptive cell transfer using intracortical injections of GFP+ ILC2s. Taken together, I will have defined the capacity of ILC2 soluble factors to polarize microglia to a reparative phenotype. This will provide the rationale to further explore ILC2 as a possible therapeutic platform in stroke and other neurologic disorders.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
