Chemerin is a recently characterized chemoattractant protein that serves as a ligand for seven-pass transmembrane, G protein‑associated receptor CMKLR1. Cells that are critical in bridging the innate and adaptive immune responses such as plasmacytoid dendritic cells (pDC) and macrophages selectively express CMKLR1 and respond to chemerin.

Chemerin circulates in the blood in a pro-form and exhibits low biological activity. The rapid activation of chemerin is a direct result of proteolytic cleavage of the chemoattractant's labile carboxy-terminus.

In collaboration with Prof. E. C. Butcher and Dr. B. A. Zabel at Stanford University, we have identified serine proteases of the inflammatory cascade such as neutrophil elastase and cathepsin G, and pathogen‑derived cysteine protease staphopain B, as potent activators of chemerin chemotactic activity (1, 2). Moreover, our collaborative work resulted in demonstrating that chemotactically active chemerin is present in lesional skin of psoriasis patients and that this chemoattractant may contribute to selective pDC recruitment to psoriatic skin (3, 4).

In addition to the regulation of specific immune cell migration (5, 6), two other functions have been ascribed to chemerin so far; chemerin appears to have anti-inflammatory effects on macrophages (7), and it functions as an adipokine in regulating  adipogenesis in vitro (8, 9).Thus chemerin regulates not only the homing behavior of pDC and macrophages but may also serve to control aspects of metabolism and fat accumulation.

These two apparently distinct functions of chemerin, regulation of leukocyte chemotaxis and adipocyte differentiation, suggest that the protein may play broader and more diverse role that was originally envisioned. Therefore, in this project we would like to propose new directions of exploration that will take us beyond the existing state-of the art and lead to:

I) DETERMINING  NOVEL FUNCTIONS OF CHEMERIN

II) THE IDENTIFICATION OF NOVEL MECHANISMS REGULATING CHEMERIN ACTIVITY

III) THE DISCOVERY OF  NOVEL MECHANISMS UNDERLYING CHEMERIN EXPRESSION.

The long-term goal of the proposed studies is to stimulate the development of therapeutic applications based on the outcomes of our studies.

References:

  1. Kulig, P., B. A. Zabel, G. Dubin, S. J. Allen, T. Ohyama, J. Potempa, T. M. Handel, E. C. Butcher, and J. Cichy. 2007. Staphylococcus aureus-derived staphopain B, a potent cysteine protease activator of plasma chemerin. J Immunol 178:3713-3720.
  2. Zabel, B. A., S. J. Allen, P. Kulig, J. A. Allen, J. Cichy, T. M. Handel, and E. C. Butcher. 2005. Chemerin activation by serine proteases of the coagulation, fibrinolytic, and inflammatory cascades. J Biol Chem 280:34661-34666.
  3. Skrzeczynska-Moncznik, J., A. Stefanska, B. A. Zabel, M. Kapinska-Mrowiecka, E. C. Butcher, and J. Cichy. 2009. Chemerin and the recruitment of NK cells to diseased skin. Acta Biochim Pol 56:355-360.
  4. Skrzeczynska-Moncznik, J., K. Wawro, A. Stefanska, E. Oleszycka, P. Kulig, B. A. Zabel, M. Sulkowski, M. Kapinska-Mrowiecka, M. Czubak-Macugowska, E. C. Butcher, and J. Cichy. 2009. Potential role of chemerin in recruitment of plasmacytoid dendritic cells to diseased skin. Biochem Biophys Res Commun 380:323-327.
  5. Wittamer, V., J. D. Franssen, M. Vulcano, J. F. Mirjolet, E. Le Poul, I. Migeotte, S. Brezillon, R. Tyldesley, C. Blanpain, M. Detheux, A. Mantovani, S. Sozzani, G. Vassart, M. Parmentier, and D. Communi. 2003. Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. J Exp Med 198:977-985.
  6. Zabel, B. A., A. M. Silverio, and E. C. Butcher. 2005. Chemokine-like receptor 1 expression and chemerin-directed chemotaxis distinguish plasmacytoid from myeloid dendritic cells in human blood. J Immunol 174:244-251.
  7. Cash, J. L., R. Hart, A. Russ, J. P. Dixon, W. H. Colledge, J. Doran, A. G. Hendrick, M. B. Carlton, and D. R. Greaves. 2008. Synthetic chemerin-derived peptides suppress inflammation through ChemR23. J Exp Med 205:767-775.
  8. Bozaoglu, K., K. Bolton, J. McMillan, P. Zimmet, J. Jowett, G. Collier, K. Walder, and D. Segal. 2007. Chemerin is a novel adipokine associated with obesity and metabolic syndrome. Endocrinology 148:4687-4694.
  9. Goralski, K. B., T. C. McCarthy, E. A. Hanniman, B. A. Zabel, E. C. Butcher, S. D. Parlee, S. Muruganandan, and C. J. Sinal. 2007. Chemerin, a novel adipokine that regulates adipogenesis and adipocyte metabolism. J Biol Chem 282:28175-28188.