Two fates of monocyte differentiation are easily identified and separable: many monocytes develop into macrophages and others become dendritic cells (DCs). One of the differences between these populations is distinct migratory behavior; macrophages are much more sessile than DCs.
We aim i n the long term to understand what determines whether monocytes differentiate into one of these fates instead of the other in a given tissue, in order to learn to manipulate monocyte fate for regulation of immune responses and chronic inflammatory conditions. Our recent demonstration that the conversion of monocytes to sessile vs. migratory fates affects the progression of atherosclerosis highlights the importance of this pursuit. Moreover, it is still not clear how significantly monocytes account for DCs that emigrate to lymph nodes under homeostatic or inflammatory conditions. A stronger fundamental understanding of normal monocyte differentiation and trafficking is needed. We will trace monocyte differentiation to DCs vs. macrophages in the steady state using a cre recombinase-expressing mouse strain to follow monocytes in homeostasis, and we will directly analyze """"""""pseudoafferent"""""""" lymph to trace monocyte-derived cells that enter peripheral lymphatic vessels (aim 1). We have also recently developed a technique to introduce a phagocytic label into circulating monocytes. This technique permits us to interogate monocyte fate in situ, including the mechanisms and consequences of conversion from one monocyte subset to another (aim 2). The use of this tracing technique also surprisingly revealed that some monocytes freshly exiting the bone marrow can have previously either derived from or have engulfed other leukocytes that recently entered the bone marrow from the periphery. Thus, monocytes which appear unactivated/""""""""naive"""""""" in the blood can be antigen-experienced before leaving the bone marrow. More work is needed to unravel this surprising finding and understand its impact on the immune system (aim 3).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049653-06
Application #
7072158
Study Section
Special Emphasis Panel (ZRG1-III (01))
Program Officer
Peyman, John A
Project Start
2000-09-15
Project End
2010-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
6
Fiscal Year
2006
Total Cost
$289,655
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Randolph, Gwendalyn J; Ivanov, Stoyan; Zinselmeyer, Bernd H et al. (2017) The Lymphatic System: Integral Roles in Immunity. Annu Rev Immunol 35:31-52
Cifarelli, Vincenza; Ivanov, Stoyan; Xie, Yan et al. (2017) CD36 deficiency impairs the small intestinal barrier and induces subclinical inflammation in mice. Cell Mol Gastroenterol Hepatol 3:82-98
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Ivanov, Stoyan; Scallan, Joshua P; Kim, Ki-Wook et al. (2016) CCR7 and IRF4-dependent dendritic cells regulate lymphatic collecting vessel permeability. J Clin Invest 126:1581-91
Lu, Qun; Yokoyama, Christine C; Williams, Jesse W et al. (2016) Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis. Cell Host Microbe 19:102-13
Durai, Vivek; Murphy, Kenneth M (2016) Functions of Murine Dendritic Cells. Immunity 45:719-736
Wu, Xiaodi; BriseƱo, Carlos G; Durai, Vivek et al. (2016) Mafb lineage tracing to distinguish macrophages from other immune lineages reveals dual identity of Langerhans cells. J Exp Med 213:2553-2565
Kim, Ki-Wook; Williams, Jesse W; Wang, Ya-Ting et al. (2016) MHC II+ resident peritoneal and pleural macrophages rely on IRF4 for development from circulating monocytes. J Exp Med 213:1951-9
Bagaitkar, Juhi; Pech, Nancy K; Ivanov, Stoyan et al. (2015) NADPH oxidase controls neutrophilic response to sterile inflammation in mice by regulating the IL-1?/G-CSF axis. Blood 126:2724-33

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