Macrophages are crucial for tissue homeostasis and play essential roles in inflammation, immunity and cancer, and therefore understanding macrophage biology is fundamental for understanding homeostasis and disease. Currently available mice that target Cre expression for the deletion of floxed genes to macrophages have significant and severe restrictions, primarily based on the promoter driving Cre expression. 1) all of the available promoters currently driving Cre in macrophages are active in the entire myeloid lineage and even other cell types, which is frequently stronger than the one in macrophages, and therefore lack macrophage specificity;2) currently available promoters only target a subset of macrophages;and 3) the two most commonly used Cre lines driven by F4/80 and LysM, are also knocked in one endogenous allele resulting in weak expression and prevent breeding of homozygous mice. The goal of this study is to develop and characterize a novel and improved transgenic mouse line to specifically target expression of Cre to macrophages. We propose to use the human CD68 promoter in combination with a macrophage-specific enhancer to drive expression of an activity-improved Cre and the dtTomato fluorescent protein from a bicistronic transcript for in vivo tracking and sorting. Transgenic mice will be extensively characterized with reporter genes and endogenous floxed genes and compared to the currently available Cre-expressing mice. Therefore our proposal to develop a novel true macrophage selective and specific Cre expressing mouse line in the C57BL/6 strain, and to make this mouse widely available to the research community, will significantly impact our current ability to study macrophages and will have significant ramifications for researchers studying macrophages in homeostasis, immunity and cancer, and will therefore enable the field to progress forward.

Public Health Relevance

Macrophages are essential for tissue homeostasis and contribute to disease. Therefore understanding macrophage biology is fundamental to advance current knowledge of these processes, which requires macrophage specific deletion of genes using the Cre recombinase. Because currently available mice expressing Cre in macrophages have severe disadvantages, our study will develop and characterize a new and substantially improved transgenic mouse with macrophage specific expression of an improved version of Cre, which will be shared with the scientific community.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Gondre-Lewis, Timothy A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Misharin, Alexander V; Cuda, Carla M; Saber, Rana et al. (2014) Nonclassical Ly6C(-) monocytes drive the development of inflammatory arthritis in mice. Cell Rep 9:591-604
Cuda, Carla M; Misharin, Alexander V; Gierut, Angelica K et al. (2014) Caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation. J Immunol 192:5548-60
Khare, Sonal; Ratsimandresy, Rojo A; de Almeida, LĂșcia et al. (2014) The PYRIN domain-only protein POP3 inhibits ALR inflammasomes and regulates responses to infection with DNA viruses. Nat Immunol 15:343-53
Rose, Shawn; Waters, Emily A; Haney, Chad R et al. (2013) High-resolution magnetic resonance imaging of ankle joints in murine arthritis discriminates inflammation and bone destruction in a quantifiable manner. Arthritis Rheum 65:2279-89
Rose, Shawn; Eren, Mesut; Murphy, Sheila et al. (2013) A novel mouse model that develops spontaneous arthritis and is predisposed towards atherosclerosis. Ann Rheum Dis 72:89-95
Perlman, Harris; Budinger, G R Scott; Ward, Peter A (2013) Humanizing the mouse: in defense of murine models of critical illness. Am J Respir Crit Care Med 187:898-900
Schwulst, Steven J; Trahanas, Diane M; Saber, Rana et al. (2013) Traumatic brain injury-induced alterations in peripheral immunity. J Trauma Acute Care Surg 75:780-8
Huang, Qi-Quan; Koessler, Renee E; Birkett, Robert et al. (2013) TLR2 deletion promotes arthritis through reduction of IL-10. J Leukoc Biol 93:751-9
Radian, Alexander D; de Almeida, Lucia; Dorfleutner, Andrea et al. (2013) NLRP7 and related inflammasome activating pattern recognition receptors and their function in host defense and disease. Microbes Infect 15:630-9
Sena, Laura A; Li, Sha; Jairaman, Amit et al. (2013) Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38:225-36

Showing the most recent 10 out of 13 publications