Inflammatory disorders can be triggered by overactive immune responses directed against host/self tissues. Indeed, neuroinflammation-associated disorders such as multiple sclerosis and stroke can be triggered and/or exacerbated by overactive immune responses against nervous tissues. It is now evident that not only cognitive disorders, but classic mental diseases such as schizophrenia and depression, are related to neuroinflammation. It is thus remarkable that infection with parasitic helminths (worms) suppresses inflammation in a variety of immune disorders. Ongoing clinical trials using worm egg in patients with multiple sclerosis are showing promising results. Hence, an understanding of helminth immunoregulatory mechanisms is likely to have enormous impact on novel strategies against inflammatory disorders. In this light, the regulation of inflammatory responses is mainly mediated via the innate immune system through antigen-presenting cells (APC) such as macrophages (M?) and microglia (MG). The functional phenotypes of MG and M? vary in response to external stimuli these cells receive through a wide variety of surface receptors. It is thought that worms or their products induce alternatively activated macrophages (AAM) that dampen inflammation and promotes tissue repair. We and others have recently documented that alternatively activated M? (AA-M?) and MG (AA-MG) have the capacity to dampen host inflammatory responses and promote wound healing and tissue repair in certain chronic neuroinflammation-related diseases. In a mouse model of neurocysticercosis (NCC) we demonstrated that AAMs are essential in containing neuropathology and disease severity. Additionally, consistent with human NCC, highly antigenic tegument galactose/ galactosamine and glucosamine containing glycan molecules of the parasite are released and taken up by host cells in the CNS environment. As lectin receptors (LRs) are the major receptors for recognition of glycan antigens, a study of their role in AA-M? and AA-MG functions in the CNS during NCC are important for understanding how NCC and neuropathological conditions can be clinically controlled. We hypothesize that glycan antigens released by parasites will lead to differential expression of specific host LRs which will play a critical role in the development and trafficking of AAM into the CNS, expression of effector molecules, and regulation of CNS immunopathology. To test this hypothesis we propose 3 specific aims.
(Aim 1) Determine the expression, kinetics, and cellular distribution of LRs during NCC by focusing on Galectin-7, Galectin-9, and SIGNR1.
(Aim 2) Identify the role of targeted LRs in AA-M? and AA-MG development, migration and functions.
(Aim 3) Elucidate the significance of targeted LRs in regulating AA-M? and AA-MG mediated control of CNS immunopathogenesis in murine NCC. Our findings in the planned studies are expected to provide new directions and approaches to manipulate AA-M? and AA-MG function to suppress inflammation in a variety of inflammatory disorders, including but not limited to CNS inflammatory diseases.
Helminth parasites infect over one third of the world's population and can cause acute and chronic pathologies. In contrast, as helminths are master regulators of host inflammatory response, it has been proposed that the rise in autoimmune diseases in the developed world could be a direct result of the successful complete elimination of parasitic helminths in these communities. Indeed, clinical trials for worm or helminth eggs as treatment of inflammatory disorders like multiple sclerosis are currently ongoing in the United States. Identification of the helminth parasite-induced immune suppressive mechanisms may provide templates for the design of novel anti-inflammatory drugs in parasitic infection as well as inflammation associated pathological conditions. In this proposal we will identify and characterize the mechanisms by which development, migration, and functions of macrophage and microglia are modulated and which in turn control CNS immunopathogenesis in murine NCC.
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