The overall objective of this project is to define the role(s) of the chemoattractant receptor chemokine like receptor-1 (CMKLR1) in regulating the pathophysiology of experimental autoimmune encephalomyelitis (EAE), a mouse model of human multiple sclerosis (MS). Myeloid cells, including macrophages and dendritic cells (DC), are major components of central nervous system (CNS) inflammatory lesions in patients with MS. Although these cells represent key mediators of tissue destruction in MS, the mechanisms that regulate their trafficking into the CNS are not entirely understood. CMKLR1 is a chemoattractant receptor that is primarily expressed by macrophages and DC, but the in vivo role of CMKLR1 expression by these cells has not been elucidated. Our preliminary data indicate an important role for CMKLR1 and its ligand chemerin in the EAE model of MS. Studies under Aim 1 will define the role(s) of CMKLR1 in the pathogenesis of EAE. These studies will have important implications for understanding how CMKLR1 contributes to macrophage and DC trafficking to the inflamed CNS. Studies in Aim 2 will define the expression and regulation of chemerin by cells resident to the CNS. These studies will define possible sources of chemerin within the CNS in vivo, where chemerin could be activated by inflammation or coagulation-associated proteases.
Aim 3 will elucidate the functional role of CMKLR1 expression by microglial cells. We will use CMKLR1-deficient mice, active and passive models of EAE, and anti-CMKLR1 blocking mAbs to investigate the contribution of CMKLR1 to disease progression in EAE. We will examine local leukocyte infiltration and functional responses to define the mechanisms by which CMKLR1 contributes to inflammation and immune responses in vivo. Cell function and cytokine production will be examined to define the mechanisms by which CMKLR1 and chemerin contribute to or modulate inflammation and immune responses in vivo. Together, the studies proposed will uncover novel pathogenic and regulatory mechanisms in MS, and may identify novel targets for therapeutic intervention. This research project has the potential to identify novel strategies for the prevention and/or treatment of autoimmune diseases, such as 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.
. This research project has the potential to identify novel strategies for the prevention and/or treatment of autoimmune diseases, such as 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.
| Graham, Kareem L; Zhang, Jian V; Lewén, Susanna et al. (2014) A novel CMKLR1 small molecule antagonist suppresses CNS autoimmune inflammatory disease. PLoS One 9:e112925 |
