Monocyte-mediated defense against microbial pathogens

Abstract

Circulating blood monocytes supply peripheral tissues with macrophage and dendritic cell (DC) precursors and, in the setting of infection, also contribute directly to immune defense against microbial pathogens. In humans and mice, monocytes are divided into two major subsets that either specifically traffic into inflamed tissues or, in the absence of overt inflammation, constitutively maintain tissue macrophage/DC populations. Inflammatory monocytes respond rapidly to microbial stimuli by secreting cytokines and antimicrobial factors, express the CCR2 chemokine receptor, and traffic to sites of microbial infection in response to monocyte chemoattractant protein (MCP)-1 (CCL2) secretion. In murine models, CCR2-mediated monocyte recruitment is essential for defense against Listeria monocytogenes, Mycobacterium tuberculosis, Toxoplasma gondii, and Cryptococcus neoformans infection, implicating inflammatory monocytes in defense against bacterial, protozoal, and fungal pathogens. Recent studies indicate that inflammatory monocyte recruitment to sites of infection is complex, involving CCR2-mediated emigration of monocytes from the bone marrow into the bloodstream, followed by trafficking into infected tissues. The in vivo mechanisms that promote chemokine secretion, monocyte differentiation and trafficking, and finally monocyte-mediated microbial killing remain active and important areas of investigation.

Figure 1

Monocyte differentiation into DCs and tissue macrophages. Macrophage-DC progenitors (MDPs) give rise to Ly6C⁺ bone marrow monocytes, which exit the bone marrow, in part guided by CCR2-dependent signals. Ly6C⁺ monocytes convert into CX3CR1⁺ monocytes, although the location of this event, in the circulation or bone marrow, remains incompletely understood. Black arrows indicate differentiation steps into tissue DCs and macrophages that occur under homeostatic conditions. Red arrows indicate differentiation steps that occur under inflammatory conditions (UV-induced skin injury, intratracheal LPS administration, or depletion of autologous CD11c⁺ cells). Dashed arrows represent steps that remain uncertain. In the case of splenic cDCs, splenic pre-DCs are the most significant upstream precursor in numeric terms (bold arrow), although MDPs and CX3CR1⁺ monocytes may contribute as well.

Figure 2

Effector functions of inflammatory monocytes. In the absence of inflammation, bone marrow CCR2⁺ monocytes have an immature phenotype and are characterized by low levels of expression of MHC class II and costimulatory molecules. Following infection, monocytes are released into the peripheral circulation and migrate to sites of inflammation, where they express distinct effector phenotypes and undergo differentiation into DCs. The effector functions of CCR2⁺ monocytes are dictated by the inflammatory context and by the nature of the invading pathogen. (a) Following infection with L. monocytogenes, monocytes are first present in the marginal zone area of the spleen and subsequently migrate to the white pulp area, where bacterial lesions are established. Monocytes undergo differentiation into TipDCs and surround infected cells, thus preventing bacterial dissemination from the lesion. While most CCR2⁺ monocytes are not infected in vivo, monocytes in the peripheral circulation may become infected and transport bacteria to the CNS. (b) In the gastrointestinal tract, infection with S. typhimurium induces influx of inflammatory monocytes and their differentiation into TipDCs. (c) Although less is known regarding the function of monocytes during M. tuberculosis infection, they are recruited to the lung and may function as a source of nitric oxide (NO). (d ) During infection with T. gondii, inflammatory monocytes become directly infected and secrete IL-12 and NO and kill parasites. T. gondii–infected monocytes may also be involved in transport of parasites to the brain.

Figure 3

Models of in vivo MCP-1-mediated monocyte recruitment. During infection, MCP-1 is produced and secreted by microbially infected or by cytokine-stimulated uninfected cells. In the first model (a), secreted MCP-1 establishes a gradient across the distance from infection site and attracts monocytes to infection sites. In an alternative model (b), the MCP-1 gradient is established not by distance from chemokine production site but rather by chemokine binding with specific GAGs. Association with GAGs increases MCP-1 concentration in specific regions and further facilitates oligomerization of MCP-1.