Macrophages (MF) are essential for immunity against pathogens, tissue homeostasis and immune regulation. Helminth infections, allergic reactions and tissue injury can induce the differentiation of alternatively activated macrophages (AAMF), which are important in promoting tissue remodeling, wound repair, T helper 2 (TH2) differentiation and parasite clearance. The differentiation process and cellular precursors of AAMF remains poorly understood. Recently, two functionally distinct subsets of monocytes and their properties have been described;(1) Ly-6C+ "inflammatory" monocytes and (2) Ly6C- "resident" monocytes. While Ly6C- monocytes populate normal tissues, they have also been shown to patrol blood vessels and extravasate rapidly into inflamed or infected tissues to promote the resolution of inflammation. Ly6C- cells are also CX3CR1-GFPhi in a CX3CR1-GFP reporter mouse and have been best characterized in models of myocardial infarction and bacterial infection. In both models, extravasated Ly6C-, CX3CR1-GFPhi monocytes have characteristics of AAMF and can promote tissue remodeling, wound healing and immune modulation. We have previously shown that helminth infection potently induces recruitment of AAMF. Others have shown that the recruitment of AAMF is critical in protecting S. mansoni infected mice from acute immunopathology in response to the eggs. We have also recently shown that sterile tissue injury can induce recruitment of AAMF in the absence of infection, through a T cell independent innate immune pathway. We have now conducted preliminary flow cytometry, confocal microscopy and intra-vital imaging studies of the liver granulomas of S. mansoni infected CX3CR1-GFP/+ mice, which suggest that AAMF are CX3CR1-GFPhi and may arise from the Ly6C-, CX3CR1-GFPhi monocytes that are patrolling the sinusoidal vessels. In this proposal, we propose to use intra-vital microscopy to observe T cell-macrophage interactions in the liver granulomas of S. mansoni infected mice. Specifically, we propose to test the hypothesis that AAMF recruited by S. mansoni eggs differentiate from CX3CR1-GFPhi, Ly6C- monocytes. As a secondary hypothesis, we propose that CD4+ T cells may play a role in recruiting or maintaining CX3CR1-GFP+ cells into the granulomas to differentiate into AAMF during chronic infection. Therefore, our specific aims are: (1) to visualize the dynamics of monocyte recruitment and macrophage differentiation in liver granulomas using the CX3CR1- GFP reporter mice;(2) to determine the role of CD4+ TH2 cells in the recruitment of CX3CR1-GFPhi cells by S. mansoni eggs in the liver granulomas. These studies will improve our understanding of monocyte recruitment and macrophage differentiation under Th2 conditions and may provide us with a framework for new interventional therapies to regulate pathogenic inflammatory Th2 responses.

Public Health Relevance

Macrophages activated under T helper type 2 conditions are important in wound healing, allergic reactions and parasite infections. How these cells are recruited into the tissues from monocytes in the blood is not clear. The goal of this project is to identify where these macrophages come from in order to design interventional strategies that could help regulate the inflammatory process during a type 2 response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI094166-02
Application #
8223147
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Wali, Tonu M
Project Start
2011-02-15
Project End
2014-07-31
Budget Start
2012-02-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$211,250
Indirect Cost
$86,250
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Gundra, Uma Mahesh; Girgis, Natasha M; Ruckerl, Dominik et al. (2014) Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct. Blood 123:e110-22
Davenport, Michael; Poles, Jordan; Leung, Jacqueline M et al. (2014) Metabolic alterations to the mucosal microbiota in inflammatory bowel disease. Inflamm Bowel Dis 20:723-31
Lee, Soo Ching; Tang, Mei San; Lim, Yvonne A L et al. (2014) Helminth colonization is associated with increased diversity of the gut microbiota. PLoS Negl Trop Dis 8:e2880
Leung, J M; Davenport, M; Wolff, M J et al. (2014) IL-22-producing CD4+ cells are depleted in actively inflamed colitis tissue. Mucosal Immunol 7:124-33
Leung, Jacqueline M; Loke, P'ng (2013) A role for IL-22 in the relationship between intestinal helminths, gut microbiota and mucosal immunity. Int J Parasitol 43:253-7
Girgis, Natasha M; Gundra, Uma Mahesh; Loke, P'ng (2013) Immune regulation during helminth infections. PLoS Pathog 9:e1003250