| Functional
Interleukin-17 Receptor A is Expressed in the Central
Nervous System and Upregulated in Experimental Autoimmune
Encephalomyelitisa
Jayasri Das Sarma1, Bogoljub Ciric1,
Ryan Marek1, Sanjoy Sadhukhan1, Jasmine Shafagh1, Denise
C. Fitzgerald1, Kenneth S. Shindler2 and A. M. Rostami1*
1Department of Neurology, Thomas Jefferson University,
Philadelphia, PA 19107.
2Department of Ophthalmology, University of Pennsylvania,
Scheie Eye Institute and FM Kirby Center for Molecular
Ophthalmology, Philadelphia, PA 19104.
Running title: Expression
and signaling of IL-17RA in the CNS
Abstract:
Interleukin-17A (IL-17A) is founding member of a novel
family of inflammatory cytokines that plays a critical
role in the pathogenesis of many autoimmune diseases,
including multiple sclerosis (MS) and its animal model,
experimental autoimmune encephalomyelitis (EAE). IL-17A
signals through IL-17RA, which is expressed in most
peripheral tissues; however, expression of IL-17RA
in the central nervous system (CNS) and its role in
CNS inflammation are not well understood. Here we
report constitutive expression of functional IL-17RA
in mouse CNS tissue. Specifically, CNS astrocytes
and microglia express IL-17RA, and IL-17A treatment
induces biological responses in these cells in vitro.
In response to exogenous IL-17A treatment, microglia
and astrocytes significantly upregulate MCP-1, MCP-5,
MIP-2 and KC chemokine secretion. Exogenous IL-17A
does not significantly alter the constitutive expression
of IL-17RA mRNA in glial cells, suggesting that upregulation
of chemokines by glial cells is due to IL-17A signaling
through constitutively expressed IL-17RA. IL-17RA
expression is significantly increased in the CNS of
mice with EAE compared to healthy mice. Our findings
suggest that IL-17RA signaling in glial cells can
play a significant role in autoimmune inflammation
of the CNS and may be a potential pathway to target
for therapeutic interventions.
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