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PAR2 (brown) expression on glial cells is increased in patients with multiple sclerosis.

An excess of proteinase receptors in the brain aggravates demyelination in multiple sclerosis (MS), suggest Noorbakhsh and colleagues on page 425. Mice lacking proteinase-activated receptor-2 (PAR₂), they show, are protected from the brain damage characteristic of experimental autoimmune encephalomyelitis (EAE), a model of MS.

PAR₂, a G protein–coupled receptor activated by trypsin-like serine proteases, is best known as the primary pain receptor in the peripheral nervous system. But this receptor is also expressed on smooth muscle cells in the gut, where it stimulates muscle contraction, and on neurons and glial cells in the brain, where it is proposed to promote cell growth and survival.

This versatile receptor can also help promote inflammation. Indeed, activation of PAR₂ on skin cells triggers the production of inflammatory cytokines, and PAR₂-deficient mice are protected against allergic dermatitis. Noorbakhsh and colleagues now show that PAR₂ also enhances inflammation in the brain.

The group noted that brain tissues from both patients with MS and mice with EAE expressed higher than normal levels of PAR₂. In mice lacking the receptor, fewer macrophages and T cells invaded the central nervous system, and demyelination was less severe—findings the authors attribute to decreased inflammatory cytokine production by resident glial cells. This finding contrasts with their earlier studies of HIV-associated dementia, in which PAR₂ actually protected neurons against cell death.

However, in HIV-associated dementia, PAR₂ expression is selectively increased on neurons and promotes cell survival. In EAE, on the other hand, the receptor is increased on glial cells (but not neurons) and promotes inflammatory gene expression.

The authors are now searching for the proteases—many of which are increased during MS and EAE—that activate PAR₂. In the meantime, they suggest that interfering with this receptor on glial cells might provide a way to limit brain degeneration in patients with MS.

hvanepps{at}rockefeller.edu

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Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis

Farshid Noorbakhsh, Shigeki Tsutsui, Nathalie Vergnolle, Leonie A. Boven, Neda Shariat, Mohammed Vodjgani, Kenneth G. Warren, Patricia Andrade-Gordon, Morley D. Hollenberg, and Christopher Power
J. Exp. Med. 2006 203: 425-435. [Abstract] [Full Text] [PDF]

This Article PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Van Epps, H. L. Search for Related Content PubMed Articles by Van Epps, H. L. Related Collections Related Article Social Bookmarking                            What's this?