Hyaluronan and Its Interactions With Immune Cells in the Healthy and Inflamed Lung

Abstract

Hyaluronan is a hygroscopic glycosaminoglycan that contributes to both extracellular and pericellular matrices. While the production of hyaluronan is essential for mammalian development, less is known about its interaction and function with immune cells. Here we review what is known about hyaluronan in the lung and how it impacts immune cells, both at homeostasis and during lung inflammation and fibrosis. In the healthy lung, alveolar macrophages provide the first line of defense and play important roles in immunosurveillance and lipid surfactant homeostasis. Alveolar macrophages are surrounded by a coat of hyaluronan that is bound by CD44, a major hyaluronan receptor on immune cells, and this interaction contributes to their survival and the maintenance of normal alveolar macrophage numbers. Alveolar macrophages are conditioned by the alveolar environment to be immunosuppressive, and can phagocytose particulates without alerting an immune response. However, during acute lung infection or injury, an inflammatory immune response is triggered. Hyaluronan levels in the lung are rapidly increased and peak with maximum leukocyte infiltration, suggesting a role for hyaluronan in facilitating leukocyte access to the injury site. Hyaluronan can also be bound by hyaladherins (hyaluronan binding proteins), which create a provisional matrix to facilitate tissue repair. During the subsequent remodeling process hyaluronan concentrations decline and levels return to baseline as homeostasis is restored. In chronic lung diseases, the inflammatory and/or repair phases persist, leading to sustained high levels of hyaluronan, accumulation of associated immune cells and an inability to resolve the inflammatory response.

Keywords: extracellular matrix; fibrosis; hyaluronan; inflammation; lung; macrophages; wound healing.

Figure 1

CD44^+/+ AMs, but not CD44^−/− AMs, have a HA coat. Frozen lung sections from CD44^+/+ and CD44^−/− mice were obtained and labeled with HABP to detect HA (red), and Siglec F, a marker of AMs (green), and cell nuclei identified by DAPI (blue). In the lower panel, the sections were treated with bovine testicular hyaluronidase (HA'se). Top and bottom row are lung sections from CD44^+/+ mice, and the middle row is from CD44^−/− mice. Images were captured on a Leica SP5 scanning laser confocal microscope, under identical acquisition settings. Images are representative of those published in Dong et al. (12).

Figure 2

Hyaluronan in the healthy and inflamed mouse lung. Frozen lung sections from CD44^+/+ mice were labeled with HABP (green) to detect HA, and stained with DAPI (blue) to label cell nuclei. On the left is a representative image of the healthy (naïve) lung where HA is present on the major bronchioles and blood vessels, with little labeling in the interstitium. The middle panel shows HA present in the lung 7 days after bleomycin induced lung inflammation (Day 7 BLM). The panel on the right is a control, showing a lung section from day 7 BLM, after treatment with hyaluronidase. All images were captured using an Olympus FV1000 scanning laser confocal microscope under identical acquisition settings. These images are similar to data described in Cheng et al. (11), Hussell and Bell (13), and Sahu and Lynn (14).