Monocyte and macrophage heterogeneity

Abstract

Peripheral-blood monocytes show morphological, antigenic and functional heterogeneity. Bone-marrow monocytes that are released into the circulation express distinct receptors for chemokines and adhesion molecules and are preferentially recruited to inflammatory lesions, where they can differentiate into macrophages or dendritic cells (DCs). These monocytes have high phagocytic activity, are known as 'inflammatory' monocytes and are identified by a CC-chemokine receptor 2 (CCR2)⁺ CX₃C-chemokine receptor 1 (CX₃CR1)^lowLy6C⁺ phenotype in mice and a CD14^hiCD16⁻CD64⁺CCR2⁺CX₃CR1^low phenotype in humans. Cells that constitute the other main subset of monocytes, which seems to be derived from the inflammatory monocytes in peripheral blood, seem to enter tissues under steady-state conditions, where they can contribute to the replenishment of tissue-resident populations of macrophages and DCs. These cells have been called 'resident' monocytes, and one of the functional differences between these monocytes and inflammatory monocytes is that resident monocytes have greater accessory activity in mixed leukocyte reactions. They are identified by a CCR2⁻CX₃CR1^hiLy6C⁻ phenotype in mice and a CD14⁺CD16⁺CD64⁻CX₃CR1^hi phenotype in humans. An intermediate phenotype of monocyte has also been observed, and these cells might be developmental intermediates. Similar to inflammatory monocytes, they respond to pro-inflammatory cues, but they also have high stimulatory activity in T-cell-stimulation assays, similar to resident monocytes. They have been suggested to be a monocyte subset that is recruited to inflammatory lesions and is prone to differentiate into DCs. They are identified by an intermediate phenotype in mice (CCR2⁺CX₃CR1^midLy6C^mid) and might be present in humans as CD14⁺CD16⁺CD64⁺ monocytes. Tissue-resident macrophage populations are replenished by a combination of local proliferation of precursors and recruitment of bone-marrow-derived precursors. In most cases, it has not been formally shown whether monocytes or specific lineage-committed precursors fulfil this role. The mechanism of replenishment of tissue-resident populations is greatly influenced by the presence of inflammation or injury, because under these conditions, a greater dependence on circulating precursors is evident in model systems.