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Inflammation: Sugar substitute is less sticky

Functional Glycomics (14 January 2010) | doi:10.1038/fg.2010.2

4F-GalNAc, an artificial monosaccharide, alters the construction of sugars coating a leukocyte surface glycoprotein, and decreases recruitment of these immune cells to sites of inflammation.

Leukocyte recruitment to sites of inflammation is disrupted by incorporation of the artificial sugar 4F-GalNAc to PSGL-1 glycans. Image courtesy of Mary O'Reilly.

Inflammation is one of the body's earliest responses to injury or illness. Swelling, one of the defining characteristics of inflammation, is caused in part by the rapid influx of white blood cells (leukocytes). Leukocytes circulate in the bloodstream until selectins, a family of glycan-binding proteins, are upregulated by the endothelial cells lining the blood vessel wall in response to inflammatory cues. Selectins bind P-selectin glycoprotein ligand 1 (PSGL-1) expressed on leukocyte surfaces, gradually slowing leukocyte flow and tethering them to the vessel wall, where they can squeeze out of the bloodstream and infiltrate surrounding tissue. Excessive inflammation can cause excess pain and lead to chronic conditions such as rheumatoid arthritis and inflammatory bowl syndrome. Writing in Blood, Sriram Neelamegham and colleagues now show that the application of 4F-GalNAc, an artificially modified sugar residue, alters PSGL-1 glycosylation, reducing selectin-mediated leukocyte adhesion and ultimately limiting immune cell recruitment to sites of inflammation.

4F-GalNAc is a synthetic analog of GalNAc, a naturally occurring sugar that forms the initial building block of O-glycans – including those linked to the PSGL-1 glycoprotein. As shown by radioactive labeling, 4F-GalNAc added to cell culture media penetrates cells and is incorporated in O-glycans in place of natural GalNAc. This switch cuts short the addition of subsequent sugars, halting PSGL-1 O-glycosylation and modifying epitopes normally recognized by selectins.

Culture of a human leukocyte cell line with 4F-GalNAc resulted in decreased selectin binding as a result of PSGL-1 epitope modification. Thus, in a system that mimics blood flow, 4F-GalNAc-treated leukocytes rolled along cell monolayers expressing selectins twice as fast as non-treated leukocytes. Likewise, fewer treated leukocytes adhered to the selectin-bearing monolayers than normal leukocytes.

In order to determine whether 4F-GalNAc inhibits leukocyte recruitment in vivo, bone marrow cells were labeled with fluorescent dye, exposed to 4F-GalNAc or a control, and injected back into a tail vein. Following injection of a chemical that induces inflammation, fewer leukocytes pre-treated with 4F-GalNAc infiltrated the site than untreated leukocytes. In a separate experiment, mice were injected daily with 4F-GalNAc or control for four days. Here, 4F-GalNAc inoculation reduced the number of leukocytes recruited to the site of inflammation by half.

Although 4F-GalNAc is incorporated into other glycoproteins as well as PSGL-1, no adverse effects were observed in treated mice. Follow-up studies will be necessary to further probe the full consequence of 4F-GalNAc treatment and to explore its therapeutic potential in alleviating inflammation.

Heather Buschman

Original research paper

  1. Marathe, D. D. et al. Fluorinated per-acetylated GalNAc metabolically alters glycan structures on leukocyte PSGL-1 and reduces cell binding to selectins. Blood (Published online 8 December 2009) doi:10.1182/blood-2009-07-231480 | Article |