Differentiation to the CCR2+ Inflammatory Phenotype In Vivo Is a Constitutive, Time-Limited Property of Blood Monocytes and Is Independent of Local Inflammatory Mediators

Abstract

It is proposed that CCR2+ monocytes are specifically recruited to inflammatory sites, whereas CCR2− monocytes are recruited to normal tissue to become resident macrophages. Whether these subsets represent separate lineages, how differential trafficking is regulated and whether monocytes undergo further differentiation is uncertain. Using a mouse model of autoimmune uveoretinitis we examined monocyte trafficking to the inflamed retina in vivo. We show that bone marrow-derived CD11b+ F4/80− monocytes require 24 to 48 h within the circulation and lymphoid system before acquiring the CCR2+ phenotype and trafficking to the inflamed retina is enabled. This phenotype, and the capacity to traffic were lost by 72 h. Monocyte CCR2 expression followed a similar time course in normal mice indicating that differentiation to an inflammatory phenotype is a constitutive, time-limited property, independent of local inflammatory mediators. Phenotypic analysis of adoptively transferred cells indicated that circulating inflammatory monocytes also differentiate into CD11c+ and B220+ dendritic cells and F4/80+ tissue macrophages in vivo. Our data supports the hypothesis of continuous extravasation and progressive differentiation over time of inflammatory monocytes in the circulation rather than replication within the actively inflamed tissue, and supports the concept of myeloid dendritic cell differentiation from trafficking monocytes under physiological conditions in vivo.

Chemokine Receptor 2-Mediated Accumulation of Fungicidal Exudate Macrophages in Mice That Clear Cryptococcal Lung Infection

“…First, the finding that ExMs present in the lung at 7 dpi expressed more Ly-6C than those present at 14 or 21 dpi is consistent with our in vitro culture of Ly-6C high monocytes and with other studies demonstrating loss of Ly-6C expression over time and as myeloid cells differentiate. 33,56,57 We also show that culture in GM-CSF alone is sufficient to induce up-regulation of CD11c, CD11b, Mac-2, CD204, and CD80; however, the expression of Mac-3 and CD86 requires additional stimulation with Cryptococcus (or lipopolysaccharide; unpublished observations, Osterholzer J). These findings suggest that ExMs are further influenced by their microenvironment.…”

“…Therefore, we evaluated ExM expression of the cell surface molecule Ly-6C as a marker of newly differentiated myeloid cells. 33,56,57 ExMs recovered at 7 dpi strongly express Ly-6C, whereas expression was diminished at 14 and 21 dpi (Figure 3). By 28 dpi, the few remaining ExMs expressed almost no Ly-6C.…”

Targeting of Gr‐1+,CCR2+ monocytes in collagen‐induced arthritis

“…It has been described that Gr-1ϩ monocytes can develop into Gr-1Ϫ monocytes (19,(22)(23)(24). For this reason, depletion of Gr-1ϩ monocytes also might eventually result in a reduced frequency of Gr-1Ϫ monocytes.…”

Privilege revisited: an evaluation of the eye's defence mechanisms

“…49 In addition, even when cells cross the vessels, they require to be activated systemically and to circulate for some time before they cross the vessels into the retina. 50 This applies to both T cells and monocytes and suggests that penetration of the barrier in inflammation requires the vessel wall to be 'made ready' for transendothelial migration, probably by weakening of the TJs. This may occur by repetitive contacts between the activated T cell and the endothelial cells and require antigen-specific signalling events in the endothelial cells, an area which requires further research.…”