Modulating Monocyte Responses to Reduce Injury after Intracerebral Hemorrhage

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH) is a devastating type of stroke affecting more than 2 million patients worldwide each year, yet there is no specific treatment available. Activation of the innate immune system at the site of hemorrhage leads to monocyte recruitment to the brain and progressive injury. In a murine model of ICH, the PI has demonstrated that the recruitment of blood-derived inflammatory monocytes to the perihematomal region leads to significant injury in the first days after ICH. However, over time, these cells contribute to phagocytosis and recovery. Interestingly, modulation of monocyte responses to inflammatory stimuli may occur in the periphery, while the monocytes are circulating and have not yet entered the brain. Whether this occurs in ICH is not known. In other models, priming by cytokines and growth factors determine whether monocytes will develop M1, proinflammatory responses, or M2 responses associated with phagocytosis and repair in response to an inflammatory environment. We propose the novel hypothesis that monocyte responses to ICH can be modulated in the systemic circulation in order to minimize early, inflammation-induced injury and expedite the recovery phase. The proposed R21 Award studies follow directly from this pre-clinical work. We will examine the effect of priming of human monocytes with inflammatory cytokines and growth factors elevated in the circulation of ICH patients on the effector responses of those cells to an inflammatory stimulus. We hypothesize that priming with interleukin-4 (IL-4) will result in enhanced phagocytosis and reduced expression of pro-inflammatory mediators (M2 response). This work will include both monocytes from both healthy controls and patients with ICH in order to maximize translational relevance. This represents a novel strategy for reducing injury after ICH, and would obviate the need for a potential therapeutic to cross the blood-brain barrier. This exploratory work will determine whether therapeutic strategies that modulate monocyte responses have the potential to improve outcomes after ICH.