Date of Completion

12-17-2014

Embargo Period

12-11-2014

Keywords

Monocytes, intracerebral hemorrhage, microglia, neuroinflammation, sterile injury

Major Advisor

Lauren H. Sansing

Associate Advisor

Louise D. McCullough

Associate Advisor

Richard E. Mains

Associate Advisor

Hector L. Aguila

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Campus Access

Abstract

Intracerebral hemorrhage (ICH) occurs when a blood vessel ruptures within the brain, usually due to uncontrolled hypertension. As blood flows into the brain and forms a hematoma, cells lyse and blood components come into direct contact with sensitive neural tissue. As a result, microglia, astrocytes, and mast cells secrete pro-inflammatory cytokines and chemokines, which induce robust recruitment of leukocytes from the blood into the region surrounding the hematoma. It has been well accepted for decades that neutrophils and T cells are among those leukocytes invading the brain after ICH. However, due to technical challenges associated with discriminating monocyte-derived macrophages from resident activated microglia, the specific monocyte response to ICH had never been described nor carefully studied. The data presented in this dissertation show that monocytes are recruited to the brain earlier than previously appreciated and are dominated by the CCR2+ Ly6Chi inflammatory monocyte subset. Their recruitment is mediated partially by α4 integrin and mice that lack inflammatory monocytes have better outcomes up to 3 days. Similarly, ICH patients with early elevations of CCL2, the principal chemokine involved in monocyte recruitment, are more likely to have worse clinical outcomes. These data suggest that monocytes not only invade the brain after ICH, but they also worsen disease outcomes acutely. However, inflammatory monocytes change phenotype over time in the mouse brain, eventually upregulating molecules involved in phagocytosis. Bead-based phagocytosis experiments show that inflammatory monocytes are more active phagocytes than microglia in two ICH-relevant assays. Moreover, mice that lack inflammatory monocytes show decreased hematoma clearance and worse later functional recovery. Altogether, the data presented in this dissertation show that inflammatory monocytes worsen ICH injury acutely, but are required for efficient hematoma clearance and long-term recovery.

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