Protection of injured or infected tissue involves the coordinated delivery of migratory leukocytes. Thus, current research efforts aim to define the mechanisms that control the movement of these cells into and out of specific tissues. Here, we will study monocytes because these cells play a central role in the orchestration and resolution of tissue inflammation, and thus represent attractive targets in therapy. Monocytes recruited to tissue are thought to originate exclusively from blood and bone marrow. However, recent work indicates that the spleen contains bona fide, undifferentiated monocytes that outnumber their blood equivalents. Also, splenic monocytes can be mobilized massively to inflammatory sites upon appropriate stimulation. These findings form the basis of our hypothesis that the spleen is a site for storage and rapid deployment of monocytes, and that splenic monocytes represent a significant resource that the body exploits to control inflammation. At present, there is a need to clarify the spleen-associated mechanisms that control monocyte homeostasis and function. In a first aim, we will measure parameters that define the biology of monocytes in the resting spleen (cell turnover, education vs maintenance, location and organization, and in vivo behavior). These studies are necessary to uncover fundamental aspects of monocyte behavior and the role of the spleen as a monocyte storage organ. In a second aim, we will define mechanisms that are employed to mobilize splenic monocytes. We will study AT-1 receptor-Angiotensin II (Ang II) signaling because it is a newly identified pathway that controls mobilization of spM. We will define the spM response to Ang II signals, and study whether modulation of Ang II signaling can be used to control the monocyte response. Our data indicate that suppression of Ang II signaling abolishes the deployment of spM and consequently suppresses the monocyte response at distant sites. Thus, these studies have important therapeutic potential. We will use state-of-the-art animal models and readouts that are available in the laboratory;these include time-lapse intravital cellular imaging to interrogate the behavior of monocytes in vivo, and profiling of 'minimally- touched'cells for comprehensive analysis in distinct tissues. We have developed and/or validated the technology over the past three years, and will now apply it to answer the biological questions relevant to monocytes. Our experiments will compare two monocyte subsets (Ly-6Chi and Ly-6Clo) because they appear to play different roles in immunity, yet their relative contributions need clarification. In vivo imaging will use newly- generated Cx3cr1gfp/+ Ccr2rfp/+ mice because monocyte subsets in these mice can be followed separately. The project will interact closely with local (Weissleder, Luster and Xavier at MGH;von Andrian at HMS) and outside (Charo at UCSF) immunology, imaging and systems biology groups.

Public Health Relevance

This research will study a newly identified, unique and very abundant cell population: splenic monocytes. We have shown that they exist, play important roles in healing of peripheral organs and in diseases, and consist of different subsets. Using novel in vivo experimental approaches we will attempt to identify key molecular players that define the biology of splenic monocytes and how they can be manipulated for new therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI084880-03
Application #
8370505
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Davidson, Wendy F
Project Start
2010-11-15
Project End
2015-10-31
Budget Start
2012-11-01
Budget End
2013-10-31
Support Year
3
Fiscal Year
2013
Total Cost
$408,151
Indirect Cost
$173,151
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Shum, Winnie W; Smith, Tegan B; Cortez-Retamozo, Virna et al. (2014) Epithelial basal cells are distinct from dendritic cells and macrophages in the mouse epididymis. Biol Reprod 90:90
Pittet, Mikael J; Nahrendorf, Matthias; Swirski, Filip K (2014) The journey from stem cell to macrophage. Ann N Y Acad Sci 1319:1-18
Squadrito, Mario Leonardo; Etzrodt, Martin; De Palma, Michele et al. (2013) MicroRNA-mediated control of macrophages and its implications for cancer. Trends Immunol 34:350-9
Cortez-Retamozo, Virna; Etzrodt, Martin; Newton, Andita et al. (2013) Angiotensin II drives the production of tumor-promoting macrophages. Immunity 38:296-308
Pucci, Ferdinando; Pittet, Mikael J (2013) Molecular pathways: tumor-derived microvesicles and their interactions with immune cells in vivo. Clin Cancer Res 19:2598-604
Cortez-Retamozo, Virna; Engblom, Camilla; Pittet, Mikael J (2013) Remote control of macrophage production by cancer. Oncoimmunology 2:e24183
Bronte, Vincenzo; Pittet, Mikael J (2013) The spleen in local and systemic regulation of immunity. Immunity 39:806-18
Etzrodt, Martin; Cortez-Retamozo, Virna; Newton, Andita et al. (2012) Regulation of monocyte functional heterogeneity by miR-146a and Relb. Cell Rep 1:317-24
Cortez-Retamozo, Virna; Etzrodt, Martin; Newton, Andita et al. (2012) Origins of tumor-associated macrophages and neutrophils. Proc Natl Acad Sci U S A 109:2491-6

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