Monocyte recruitment during infection and inflammation

Abstract

Monocytes originate from progenitors in the bone marrow and traffic via the bloodstream to peripheral tissues. During both homeostasis and inflammation, circulating monocytes leave the bloodstream and migrate into tissues where, following conditioning by local growth factors, pro-inflammatory cytokines and microbial products, they differentiate into macrophage or dendritic cell populations. Recruitment of monocytes is essential for effective control and clearance of viral, bacterial, fungal and protozoal infections, but recruited monocytes also contribute to the pathogenesis of inflammatory and degenerative diseases. The mechanisms that control monocyte trafficking under homeostatic, infectious and inflammatory conditions are being unravelled and are the focus of this Review.

Conflict of interest statement

Competing interests statement

The authors declare no competing financial interests.

Figures

Figure 1. Trafficking of circulating monocyte subsets

Macrophage and dendritic cell precursors (MDPs) in the bone marrow give rise to LY6Chi monocytes, which can serve as an intermediate for LY6Clow monocyte generation. LY6Chi monocytes exit the bone marrow in a CC-chemokine receptor 2 (CCR2)-dependent manner and are recruited to inflamed tissues. Here, they can differentiate into TNF- and iNOS-producing dendritic cells (TIP DCs), inflammatory macrophages or inflammatory DCs, some of which can subsequently migrate to draining lymph nodes. LY6Clow monocytes patrol the blood vessel lumen by associating with the vascular endothelium. LY6Clow monocytes are also recruited to sites of inflammation and possibly contribute to wound healing by differentiating into alternatively activated macrophages. Under certain experimental conditions, LY6Chi monocytes can give rise to Langerhans cells in the skin, microglia in the central nervous system, and CX3C-chemokine receptor 1 (CX3CR1)+ mononuclear phagocytes in the intestinal lamina propria, where they can sample the gut lumen by extending dendrites between intestinal epithelial cells. In the absence of inflammation, some circulating LY6Chi monocytes return to the bone marrow. The spleen functions as a reservoir for monocytes outside the bone marrow. Following myocardial infarction, monocytes are released from splenic reservoirs, and LY6Chi monocytes are selectively recruited to the injured heart.

Figure 2. Monocyte recruitment is crucial for defence against a broad range of pathogenic microorganisms

Infections with diverse pathogens, including bacteria, parasites, fungi and viruses, induce the recruitment of LY6Chi monocytes to sites of infection. For most pathogens (including those listed in the blue boxes), CC-chemokine receptor 2 (CCR2)-mediated monocyte recruitment enhances resistance to infection. However, during some infections (such as Trypanosoma brucei or influenza virus infection; listed in the red boxes), CCR2-mediated recruitment of monocytes is deleterious and enhances pathology.

Figure 3. Pro-inflammatory cytokines and TLR ligands promote the emigration of LY6Chi monocytes from the bone marrow

Monocyte emigration from the bone marrow during the early stage of infection with Listeria monocytogenes is normal in mice that lack either myeloid differentiation primary response protein 88 (MYD88; which is required for most responses to Toll-like receptor (TLR) ligands) or the type I interferon receptor (IFNAR). However, the combined loss of MYD88 and IFNAR impairs monocyte emigration from the bone marrow. IFN, interferon.

Figure 4. Models of CCL2-mediated emigration of LY6Chi monocytes from the bone marrow

Release of LY6Chi monocytes from the bone marrow during Listeria monocytogenes infection is driven by CC-chemokine ligand 2 (CCL2). CCL2 is produced by mesenchymal stem cells (MSCs) and CXCL12-abundant reticular (CAR) cells following stimulation with circulating Toll-like receptor (TLR) ligands. Two models are proposed for the emigration of monocytes following CCL2 expression by these bone marrow stromal cells. In the first model, CCL2 production in the bone marrow increases monocyte chemokinesis, thereby increasing the likelihood that monocytes will come into contact with blood vessels. Subsequent movement of monocytes into the lumen may be independent of CC-chemokine receptor 2 (CCR2) (a). In the second model, CCL2 produced in proximity to vascular sinuses binds to glycosaminoglycans (GAGs) and forms a chemokine gradient that attracts monocytes to the abluminal aspect of the endothelium and then guides their transmigration into the circulation (b).