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Blood, 15 August 2008, Vol. 112, No. 4, pp. 929-930.
Teasing out monocyte trafficking mechanismsBETH ISRAEL DEACONESS MEDICAL CENTER (BIDMC) OF HARVARD MEDICAL SCHOOL
In this issue of Blood, Xu and colleagues demonstrate that mechanisms controlling monocyte recirculation through peripheral and lymphoid tissues alter in a systemic fashion during inflammation, with CD62-L and CD44 playing key roles.
Monocyte trafficking critically contributes to inflammatory and autoimmune disease. For example, in atherosclerosis, monocytes become recruited to inflamed arteries, where they differentiate into macrophages that ultimately become pathogenic lipid-laden foam cells.3 In rheumatoid arthritis, monocyte trafficking to, and differentiation in, the joints has been suggested to feed the autoimmune cycle by providing a source for the high levels of synovial-fluid DCs that ultimately stimulate tissue-damaging autoreactive effector cells.4 Importantly, however, contrasting the extensive studies of lymphocyte trafficking and homing, relatively little remains known about the complexities and molecular mechanisms directing monocyte trafficking in vivo during inflammation. Xu and colleagues designed a study to begin to address this paucity by using a noninvasive in vivo retinal imaging approach in the context of experimental autoimmune uveoretinitis (EAU). Thus, the trafficking of adoptively transferred GFP+ monocytes through inflamed retinal venules was characterized in the absence and presence of antibodies that block the function of specific leukocyte-trafficking adhesion molecules. It was found that blockade of CD62-L (L-selectin) or CD44 (the hyaluronan receptor) abrogated monocyte rolling, firm adhesion, and ultimate infiltration into the retina, whereas blockage of PSGL-1 (a ligand for P-, E- and L-selectins) and LFA-1 (receptor of ICAM-1) had either partial or no effect, respectively, on these parameters. The findings are in general agreement with a variety of previous studies in other models. Strikingly, and somewhat surprisingly, CD62-L and CD44 blockade also lead to a rapid and profound depletion of monocytes from the circulation. These effects were inflammation specific, as they were observed in the setting of EAU but not in healthy control animals. Moreover, these treatments caused monocytes to accumulate in specific lymphoid tissues, with CD44 blockade causing concomitant retention in the lymph nodes and depletion from the spleen, and CD62-L blockade causing accumulation in the spleen and depletion from lymph nodes. Interestingly, these effects were also systemic, as monocyte sequestration (with CD44 blockade) was observed in distant, as well as draining, cervical lymph nodes. From these results, it was concluded that mechanisms controlling monocyte recirculation through peripheral and lymphoid tissues alter in a systemic fashion during inflammation, and that under such conditions, CD62-L and CD44 play important roles in maintaining monocytes within circulation. This study provides a novel hypothesis and provocative findings. Several of these observations were unexpected and remain unexplained. For example, the observations with CD44 demonstrate a novel and clearly important role for CD44 in monocyte trafficking during inflammation, but the mechanisms driving their reduction in the spleen are unclear. Similarly, how CD62-L blockade drives monocyte accumulation in spleen in the setting of EAU but not in control mice remains mysterious. Such issues suggest a previously unappreciated complexity in the mechanisms and regulation of monocyte trafficking. Thus, in addition to providing new insights, the work by Xu et al provides interesting new questions for future studies.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
REFERENCES
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
