The overall objective of this project is to define the role of chemerin receptors CMKLR1 and CCRL2 in leukocyte trafficking, function, and the pathophysiology of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Preliminary results suggest that CMKLR1 is an integrin-triggering chemoattractant receptor expressed by macrophages, NK cells, and upregulated by activated dendritic cells;CCRL2 is a non-signaling chemerin "delivery" receptor expressed by mast cells, activated macrophages and endothelial cells that binds chemerin and serves to regulate the bioavailability of the attractant;and that the chemerin receptors play critical roles in modulating inflammatory responses in vivo. Studies under Aim 1 will determine if chemerin can induce CMKLR1-mediated integrin triggering and rapid adhesion in macrophages and NK cells. These studies will have important implications for understanding how CMKLR1 contributes to macrophages and NK trafficking in vivo where chemerin is activated by inflammation or coagulation-associated proteases. Studies under Aim 2 test the hypothesis that CCRL2 is a non-signaling chemerin "delivery" receptor that serves to concentrate and present active chemoattractant. These studies will elucidate the functional significance of CCRL2 in regulating chemerin activity and its signaling via CMKLR1 in vivo.
Aim 3 will define the roles of CMKLR1 and CCRL2 in the pathophysiology of experimental autoimmune encephalomyelitis (EAE). Mice genetically deficient in CMKLR1 or CCRL2, as well as anti-mCMKLR1 blocking mAbs, will be used to investigate the contribution of these receptors to disease progression in animals. Local leukocyte infiltration, function, and cytokine production will be examined to define the mechanisms by which the receptors contribute to or modulate inflammation and immune responses in vivo. Together, the studies proposed promise to define a key regulatory mechanism in macrophage, mast cell, and NK cell biology and function. They may lead to novel targets or approaches for the prevention or treatment of autoimmune disease.

Public Health Relevance

This research project has the potential to identify novel targets for the prevention and/or treatment of autoimmune diseases, such multiple sclerosis. This project will improve our understanding of white blood cell trafficking, and may offer new methods for therapeutically altering the accumulation and/or function of critical white blood cell populations at sites of tissue damage and inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI079320-05
Application #
8490283
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Miller, Lara R
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$296,842
Indirect Cost
$89,550
Name
Palo Alto Institute for Research & Edu, Inc.
Department
Type
DUNS #
624218814
City
Palo Alto
State
CA
Country
United States
Zip Code
94304
Tang, Mi; Huang, Chen; Wang, Yu-Fei et al. (2016) CMKLR1 deficiency maintains ovarian steroid production in mice treated chronically with dihydrotestosterone. Sci Rep 6:21328
Lee, Sung Kyun; Kim, Sang Doo; Kook, Minsoo et al. (2015) Phospholipase D2 drives mortality in sepsis by inhibiting neutrophil extracellular trap formation and down-regulating CXCR2. J Exp Med 212:1381-90
Banas, Magdalena; Zegar, Aneta; Kwitniewski, Mateusz et al. (2015) The expression and regulation of chemerin in the epidermis. PLoS One 10:e0117830
Pachynski, Russell K; Scholz, Alexander; Monnier, Justin et al. (2015) Evaluation of Tumor-infiltrating Leukocyte Subsets in a Subcutaneous Tumor Model. J Vis Exp :
Zabel, Brian A; Rott, Alena; Butcher, Eugene C (2015) Leukocyte chemoattractant receptors in human disease pathogenesis. Annu Rev Pathol 10:51-81
Zabel, Brian A; Kwitniewski, Mateusz; Banas, Magdalena et al. (2014) Chemerin regulation and role in host defense. Am J Clin Exp Immunol 3:1-19
Monnier, Justin; Zabel, Brian A (2014) Anti-asialo GM1 NK cell depleting antibody does not alter the development of bleomycin induced pulmonary fibrosis. PLoS One 9:e99350
Tu, Hua; Burke, Thomas M; Oderup, Cecilia et al. (2014) Robust expansion of dendritic cells in vivo by hydrodynamic FLT3L-FC gene transfer. J Immunol Methods 413:69-73
Li, Lei; Huang, Chen; Zhang, Xu et al. (2014) Chemerin-derived peptide C-20 suppressed gonadal steroidogenesis. Am J Reprod Immunol 71:265-77
Li, Lei; Ma, Ping; Huang, Chen et al. (2014) Expression of chemerin and its receptors in rat testes and its action on testosterone secretion. J Endocrinol 220:155-63

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