New Mechanisms and Pathways for Monocyte Recruitment

A great deal of recent research has identified chemoat-tractants and cellular activators responsible for neutrophil trafficking into inflamed tissues, as well as for lymphocyte homing to secondary lymphoid organs in the steady state and into foci of chronic inflammation (1–5). Considerably less is known about the molecules regulating the trafficking of monocytes, particularly the constitutive trafficking of monocytes through tissues in health and the recruitment of monocytes to lymph nodes in disease. Two articles in this issue of The Journal of Experimental Medicine (6, 7) and one in a recent issue (8) shed some light on this subject and also prompt some questions for future investigation. Under steady-state conditions in mice about half of the circulating monocytes leave the bloodstream each day (9, 10). Effete monocytes are destroyed in the spleen, but a considerable fraction of circulating monocytes enter the tissues of the body, differentiating into tissue macrophages (9, 10) or dendritic cells (DCs; references 11 and 12). The lifespan of individual tissue macrophages is controversial, but the permanence of tattoos attests to the ability of a stable or self-renewing population of macrophages to be maintained in place for the lifetime of the individual. In contrast, immature DCs within the tissues are able to leave via afferent lymphatic vessels for the draining lymph nodes, where they mature, present antigen to T cells, and die within a few days of arrival. Thus, a large fraction of monocytes can potentially be cleared as a byproduct of immune surveillance. In mice responding to an inflammatory challenge, the number of monocytes leaving the circulation per day is at least double (10). The half-life of circulating monocytes in humans is about three times longer than in mice (13), but the thousandfold greater monocyte mass in humans means that ‫ف‬ 340 million monocytes leave the circulation each day. Monocyte Recruitment into Tissues. While chemokines such as monocyte chemotactic protein (MCP)-1 (CCL2) have been demonstrated to recruit monocytes into foci of active inflammation (14–16), it has not been clear whether monocytes use the same molecular signals to emigrate into tissues as part of the constitutive or steady-state efflux from blood. Prerequisites for a molecule that recruits monocytes into healthy tissues should include (i) constitutive expression of the chemoattractant by cells of that tissue (i.e., epithelia or stroma), (ii) preferential or selective response of monocytes to this molecule, and (iii) the ability to recruit monocytes into tissue without …