Role of CD44 and Hyaluronan in Neutrophil Recruitment

Abstract

Lymphocyte CD44 interactions with hyaluronan localized on the endothelium have been demonstrated to mediate rolling and regulate lymphocyte entry into sites of chronic inflammation. Because neutrophils also express CD44, we investigated the role of CD44 and hyaluronan in the multistep process of neutrophil recruitment. CD44−/− and wild-type control mice were intrascrotally injected with the neutrophil-activating chemokine, MIP-2, and leukocyte kinetics in the cremasteric microcirculation were investigated 4 h subsequently using intravital microscopy. Neither the rolling flux nor the rolling velocities were decreased in CD44−/− mice relative to wild-type mice. In vitro, neutrophils did not roll on the CD44 ligand hyaluronan, consistent with the in vivo data that CD44/hyaluronan did not mediate rolling. However, the number of adherent leukocytes in the venule was decreased by 65% in CD44−/− mice compared with wild-type mice. Leukocyte emigration was also greatly decreased in the CD44−/− mice. The same decrease in adhesion and emigration was observed in the wild-type mice given hyaluronidase. Histology revealed neutrophils as being the dominant infiltrating population. We generated chimeric mice that express CD44 either on their leukocytes or on their endothelium and found that CD44 on both the endothelium and neutrophils was important for optimal leukocyte recruitment into tissues. Of those neutrophils that emigrated in wild-type and CD44−/− mice, there was no impairment in migration through the interstitium. This study suggests that CD44 can mediate some neutrophil adhesion and emigration, but does not appear to affect subsequent migration within tissues.

The role of CD44 in the acute and resolution phase of the host response during pneumococcal pneumonia

“…Several studies have shown a positive role of CD44 in inflammatory cell recruitment, 10,25,[36][37][38][39][40][41] whereas other investigations reported enhanced inflammatory cell migration in the absence of CD44. 8,9,24,35 This discrepancy is probably because of the differences in the cell type studied, the stimulus and organ involved, and the severity of the insult.…”

Stretch-induced human myometrial cytokines enhance immune cell recruitment via endothelial activation

“…51 In addition, CD44 (which is constitutively expressed by immune cells) was shown to be involved in the recruitment of monocytes and neutrophils to the site of inflammation. 52,53 CD44-hyaluronic acid interaction could be induced by inflammatory stimuli such as cytokines. 54 CD44 protein was recently found to be increased on peripheral leukocytes from term pregnant women.…”

Hyaluronan Anchored to Activated CD44 on Central Nervous System Vascular Endothelial Cells Promotes Lymphocyte Extravasation in Experimental Autoimmune Encephalomyelitis

“…For example, in dermal ECs, TLR4 signal induced by HA fragments increases expression of the cell adhesion molecule ICAM-1 and the chemokine MIP-2, which are involved in the recruitment of neutrophils (42). CD44/HA interactions mediate neutrophil and lymphocyte adhesion and migration across endothelium (43). Additionally, siRNA inhibition of endogenous hyaluronidases in fibroblasts subjected to collagen-induced arthritis decreases TLR4 expression, NF-B activation, and IL-1␤ production elicited by TNF␣ stimulation (44).…”