Abstract

Semaphorins are extracellular/transmembrane
signaling proteins essential for the development and maintenance of many
tissues. In the CNS semaphorins are key regulators of neuronal structure and
function as axon guidance molecules. Semaphorin signaling occurs predominantly
through Plexin receptors and results in changes in the cytoskeletal machinery. A
growing body of evidence suggests an association of semaphorins with a range of
neurological disorders.

PlexinB1 is expressed in neural tissue and is
the high affinity receptor for Semaphorin 4D (Sema4D). It has previously been
shown that Sema4D- or PlexinB1-deficient mice exhibit resistance to
experimental autoimmune encephalomyelitis, and that Sema4D-PlexinB1 interaction
leads to microglial activation. Here we study the interaction between Sema4D
and PlexinB1 in microglia and astrocytes. Glial cells exert complex functions
essential for neural activity in the CNS, and dysfunctional activation of glial
cells has been associated with various neuroinflammatory disorders.

We demonstrate that Sema4D is expressed on
immune cells and PlexinB1 in primary mouse microglia and astrocytes. Exposure
of glial cells to Sema4D in the presence of other co-activators elicits
increased iNOS expression and activity, as well increased production of
inflammatory cytokines from these cells. Enhanced activation of microglia and
astrocytes following Sema4D-PlexinB1 binding further validates this interaction
as a potential therapeutic target for neuroinflammatory disease.