Monocyte Trafficking and Antimicrobial Defense

The term ’monocyte’ refers to a subset of circulating white blood cells that differentiate into a range of tissue macrophages and dendritic cells. Bloodstream monocytes derive from (Figure 1) precursors in the bone marrow and are subdivided into subsets that differ in size, trafficking, innate immune receptor expression and in their ability to differentiate following stimulation.

Monocyte subsets and trafficking

Figure 1 — Monocyte subsets and trafficking. From Serbina et al. Annual Review of Immunology (2008) 26:421-452.

Our laboratory investigates inflammatory monocytes, a subset that mediates host antimicrobial defenses but also enhances tissue destruction during some infections. Inflammatory monocytes express the CCR2 chemokine receptor and respond to the chemokines MCP1 and MCP3. Our laboratory discovered that CCR2 stimulates monocyte emigration from the bone marrow into the bloodstream during infection with Listeria monocytogenes. Since L. monocytogenes predominantly infects the spleen and the liver, it was unclear how monocyte emigration from the bone marrow was orchestrated. Our laboratory has generated reporter and conditional knockout mouse strains and discovered that infection of mice rapidly induces expression of MCP1 by stromal cells in the bone marrow and that local MCP1 expression in the bone drives inflammatory monocytes from the cellular compartment into the bloodstream. Many questions about this process remain unanswered and are the focus of our laboratory. For example, how does MCP1 expression in the bone marrow induce inflammatory monocyte emigration? How do inflammatory monocytes migrate from the cellular compartment across the endothelium into the bloodstream?

Once monocytes enter the bloodstream, it has been unclear how they localize to foci of bacterial infection in peripheral tissues. Recent work in our laboratory demonstrated that inflammatory monocyte trafficking to the liver is chemokine receptor independent and largely mediated by adhesion molecules. Our laboratory is investigating how bacterial infection and the induction local inflammatory cytokines influences monocyte trafficking to sites of infection and we are determining which monocyte effector functions are critical for bacterial clearance.

Monocytes influence CD4 T cells responses and, in their absence, CD4 T cell responses are attenuated and differentiation is aberrant. We have investigated the role of inflammatory monocytes in the activation and differentiation of CD4 T cells responding to Aspergillus fumigatus and, more recently, have shifted our focus to studies of how inflammatory monocytes influence CD4 T cell priming and differentiation during Mycobacterium tuberculosis infection. While our studies have demonstrated that inflammatory monocytes and their derivative cell populations transport microbes from the lung to draining lymph nodes during early infection and that they influence CD4 T cell differentiation in the lung at later stages of infection, many questions about the interactions between inflammatory monocytes and CD4 T cells remain. Do monocytes carrying microbes to lymph nodes differentiate into dendritic cells and directly prime naïve CD4 T cells or do they transport antigens and transfer them to classical DCs? How is the interaction between inflammatory monocytes and responding CD4 T cells in peripheral tissues mediated and how do monocytes influence the trafficking and differentiation of CD4 T cells in peripheral tissues.

Shi C, Velazquez P, Hohl TM, Leiner I, Dustin ML, Pamer EG. Monocyte trafficking to hepatic sites of bacterial infection is chemokine-independent and directed by focal ICAM-1 expression. Journal of Immunology. 2010 Jun 1;184(11):6266-74.

Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol. 2011 Oct 10; 11(11):762-74.

Shi C, Jia T, Mendez-Ferrer S, Hohl TM, Serbina NV, Lipuma L, Leiner I, Li MO, Frenette PS, Pamer EG. Bone Marrow Mesenchymal Stem and Progenitor Cells Induce Monocyte Emigration in Response to Circulating Toll-like Receptor Ligands. Immunity. 2011; 34(4):590-601.

Shi C, Hohl TM, Leiner I, Equinda MJ, Fan X, Pamer EG. Ly6G+ neutrophils are dispensable for defense against systemic Listeria monocytogenes infection. Journal of Immunology. 2011; 187(10):5293-8.

Ryder M, Gild M, Hohl TM, Pamer E, Knauf J, Ghossein R, Joyce JA, Fagin JA. Genetic and pharmacological targeting of CSF-1/CSF-1R inhibits tumor-associated macrophages and impairs BRAF-induced thyroid cancer progression. PLoS One. 2013; 8(1): e54302

Samstein M, Schreiber HA, Leiner IM, Susac B, Glickman MS, Pamer EG. Essential yet limited role for CCR2+ inflammatory monocytes during Mycobacterium tuberculosis specific T cell priming. Elife. 2013 Nov 12; 2:e01086.

Franklin RA, Liao W, Sarkar A, Kim MV, Bivona MR, Liu K, Pamer EG, Li MO. The cellular and molecular origin of tumor-associated macrophages. Science. 2014 May 23; 344(6186):921-925.

Xiong H, Carter RA, Leiner IM, Tang YW, Chen L, Kreiswirth BN, Pamer EG. Distinct contributions of neutrophils and CCR2+ monocytes to pulmonary clearance of different Klebsiella pneumoniae strains. Infection and Immunity. 2015 Jun 8; Epub ahead of print.