Inflammatory monocytes are essential for Innate immune defense against bacterial, fungal, protozoal andviral pathogens. To be effective, monocytes must be recruited from the bone marrow to sites of infection.The mechanisms tiiat drive monocyte recruitment, however, are poorly understood and are the focus of ourproposed studies. Our laboratory has demonstrated that the CCR2 chemokine receptor and its ligandsMCP1 and MCP3 are required for monocyte emigration from the bone marrow during Listeriamonocytogenes infection. How infection in the spleen and liver induces monocyte emigration from the bonemarrow, however, remains mysterious. The goal ofthe proposed studies is to determine how infections andcirculating microbial molecules promote monocyte emigration from the bone marrow into the bloodstream.
Our first aim i s to characterize expression of MCPl by cells in the bone marrow following systemic LPSinjection and during Listeria monocytogenes infection. These studies will use a recentiy generated MCPlreporter mouse strain and a mouse strain in which MCP1 can be conditionally deleted. Our proposedexperiments will determine whether specific deletion of MCPl in these cell populations impairs monocytetrafficking. The second specific aim is to investigate in vivo MCP3 production in bone marrow and peripheraltissues and determine its role in monocyte recruitment. We will generate a conditional MCP3knockout/reporter mouse strain to determine which cells in bone marrow and peripheraltissuesorchestratemonocyte migration by expressing MCP3. The third specific aim is to investigate the roles of TLR ligandsand inflammatory cytokines as inducers of MCP1 and MCP3 expression by stromal and hematopoietic cellsin the bone marrow. We will investigate the induction of MCPl and MCP3 in response to LPS or L.monocytogenes infection in reporter mice lacking MyD88, TNF, type I interferon receptor and IFN-gamma.Our studies will provide fundamental insights into the in vivo mechanisms that promote monocyterecruitment to sites of inflammation.

Public Health Relevance

Inflammatory monocytes combat infection but they also contribute to atherosclerosis and autoimmunediseases. Our studies will identify mechanisms that promote trafficking of inflammatory monocytes frombone marrow to sites of infection. Deciphering mechanisms driving monocyte trafficking may lead to newapproaches to enhance immune defense against infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Mills, Melody
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Sloan-Kettering Institute for Cancer Research
New York
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