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CD44 and hyaluronan binding in macrophages and dendritic cells Poon, Grace Fong-Ting


Hyaluronan is a glycosaminoglycan present in pericellular and extracellular matrices. Hyaluronan production and binding are tightly regulated during an immune response yet its effects on immune cells, particularly macrophages and dendritic cells, are not fully understood. CD44 is the major surface receptor for hyaluronan, but not all CD44-expressing cells have the ability to bind hyaluronan. Here I demonstrate that hyaluronan binding is dynamically regulated during macrophage activation as well as dendritic cell differentiation, and CD44 provides macrophages with a selective advantage in the alveolar space that correlates with hyaluronan binding. Inflammatory macrophages activated with lipopolysaccharide plus interferon gamma bound higher levels hyaluronan compared to alternatively activated macrophages polarized with interleukin 4 by modifying chondroitin sulfation on CD44, and these macrophages differ in their ability to take up hyaluronan. In GM-CSF bone marrow-derived dendritic cell cultures, hyaluronan binding identified an immature population that was CD11c+ MHC IImid/low, highly proliferative and did not mature into MHC IIhigh cells. The removal of hyaluronan with hyaluronidase inhibited proliferation of the hyaluronan binding cells and promoted the maturation of dendritic cells. Furthermore, the hyaluronan binding cells had several macrophage characteristics and were retained in the alveolar space while the MHC IIhigh, low hyaluronan binding dendritic cells migrated to the lymph node upon inflammation. These results suggest a role for hyaluronan in cell proliferation and retention in the alveolar space. In vivo, peritoneal, splenic and lung interstitial macrophages bound low or no detectable levels of hyaluronan whereas alveolar macrophages constitutively bound high levels of hyaluronan. The alveolar space promoted hyaluronan binding, as instillation of peritoneal macrophages into the lung upregulated their ability to bind hyaluronan. During lung inflammation, the hyaluronan binding population in the alveolar space was initially reduced and then restored upon resolution as a result of macrophage proliferation. In competition assays, CD44 provided hyaluronan binding macrophages with an advantage in the alveolar space. Collectively, this study reveals a novel role for CD44 in the maintenance of macrophages in the alveolar space and suggests that hyaluronan binding is induced at GM-CSF rich environments to help retain tissue macrophages at the site and promote their self-renewal.

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