The innate immune system is composed of """"""""hard-wired"""""""" elements of immunity, such as natural killer cells, phagocytes, defensins, and complement, that mount an initial protective response to kill, clear and/or limit deleterious invaders. A relatively newly defined family of proteins, designated as defense collagens, is an example of the constitutive recognition components of the innate system. Each of these defense collagens recognizes selective motifs displayed on pathogenic material, and mediates a protective response. Interaction of several soluble defense collagens with a novel transmembrane protein, C1qRP, has been shown to facilitate the rapid ingestion of suboptimally opsonized particles, a potentially critical mechanism in host defense particularly at early stages of infection/disease when little or no adaptive response is yet present. In addition, this receptor, which is selectively expressed on monocytes, macrophages, neutrophils, endothelial cells and platelets, may contribute to the rapid clearance of apoptotic and/or damaged cells, a critical process during tissue remodeling. This would be particularly advantageous, as ligation of this receptor by monocytes does not trigger proinflammatory cytokine production. This proposal will focus, first, on determining the physiologic role of this receptor by generating, characterizing, and testing specific hypotheses in a murine model in which this gene has been ablated, and secondly, on the intracellular signaling mechanisms involved in triggering enhanced phagocytosis and in regulating proinflammatory cytokine induction. The ability of C1qRP to regulate the phagocytic capacity of myeloid cells could be extremely valuable as a prophylactic treatment for individuals at risk for infection, such as individuals with genetic immunodeficiencies or pathogen-induced immunosuppression, patients undergoing cancer chemotherapy, or patients undergoing high risk surgery. However, this surface molecule also has the potential for modulation of processes contributing to damaging inflammation (such as vasculitis, nephritis, neurodegeneration), and understand physiologic clearance of apoptotic cells and/or cellular debris which would be potentially relevant to both inflammation and certain types of autoimmunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI041090-05
Application #
6199431
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Adams, Ken
Project Start
1996-07-01
Project End
2005-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
5
Fiscal Year
2000
Total Cost
$282,709
Indirect Cost
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
Clarke, Elizabeth V; Weist, Brian M; Walsh, Craig M et al. (2015) Complement protein C1q bound to apoptotic cells suppresses human macrophage and dendritic cell-mediated Th17 and Th1 T cell subset proliferation. J Leukoc Biol 97:147-60
Clarke, Elizabeth V; Tenner, Andrea J (2014) Complement modulation of T cell immune responses during homeostasis and disease. J Leukoc Biol 96:745-56
Ueno, Norikiyo; Harker, Katherine S; Clarke, Elizabeth V et al. (2014) Real-time imaging of Toxoplasma-infected human monocytes under fluidic shear stress reveals rapid translocation of intracellular parasites across endothelial barriers. Cell Microbiol 16:580-95
Benoit, Marie E; Hernandez, Michael X; Dinh, Minhan L et al. (2013) C1q-induced LRP1B and GPR6 proteins expressed early in Alzheimer disease mouse models, are essential for the C1q-mediated protection against amyloid-? neurotoxicity. J Biol Chem 288:654-65
Stephan, Alexander H; Madison, Daniel V; Mateos, José María et al. (2013) A dramatic increase of C1q protein in the CNS during normal aging. J Neurosci 33:13460-74
Clarke, Elizabeth V; Benoit, Marie E; Tenner, Andrea J (2013) Purification of Human Monocytes and Lymphocyte Populations by Counter Current Elutriation- A Short Protocol. Bio Protoc 3:
Benoit, Marie E; Clarke, Elizabeth V; Tenner, Andrea J (2013) C1q Binding to and Uptake of Apoptotic Lymphocytes by Human Monocyte-derived Macrophages. Bio Protoc 3:
Benoit, Marie E; Clarke, Elizabeth V; Morgado, Pedro et al. (2012) Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells. J Immunol 188:5682-93
Benoit, Marie E; Tenner, Andrea J (2011) Complement protein C1q-mediated neuroprotection is correlated with regulation of neuronal gene and microRNA expression. J Neurosci 31:3459-69
Fraser, Deborah A; Pisalyaput, Karntipa; Tenner, Andrea J (2010) C1q enhances microglial clearance of apoptotic neurons and neuronal blebs, and modulates subsequent inflammatory cytokine production. J Neurochem 112:733-43

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