ReviewMyeloid cell population dynamics in healthy and tumor-bearing mice
Introduction
Myeloid cell subpopulations − polymorphonuclear neutrophils (PMNs), monocytes (MOs), macrophages (Mϕs; extravasated blood MOs are defined as Mϕs) and dendritic cells (DCs) − are key mediators of inflammatory and immune responses [1]. They share several common properties, namely phagocytic activity, immunophenotype, origin and relatively rapid turnover. However, they also have distinct roles in inflammatory responses: PMNs and Mϕs play an important role in the elimination of pathogens and components of damaged tissue via phagocytosis; PMNs amplify inflammation by releasing cytotoxic granules, whereas Mϕs terminate inflammation and restore tissue integrity after removal of the inflammatory stimuli [2], [3]. Myeloid cells also play an important role in adaptive immune responses; DCs activate antigen specific T cells during inflammatory responses, whereas PMNs, Mϕs and some immature myeloid cells suppress T cell responses, which has led to the concept of myeloid-derived suppressor cells (MDSCs) [4], [5], [6], [7]. Balance between myeloid cell subpopulations is critical to achieve optimal immune responses and host defense.
Tumors are environments of unresolved inflammation initiated by malignant cells. During tumor development, MDSCs accumulate massively in both tumor and secondary lymphoid tissues, where they regulate inflammatory and immune responses [5], [6], [7]. Since the systemic accumulation of myeloid cells is often associated with poor prognosis and immunosuppression, MDSCs have attracted considerable interest as potential targets in the development of cancer therapies that may abrogate MDSC-mediated immunosuppression [8].
Tumor-induced MDSC accumulation is due to increased MDSC proliferation and differentiation in bone marrow, and subsequent migration from bone marrow to blood and from blood to target tissues [9]. This increased turnover of MDSCs is regulated by inflammatory mediators produced within the tumor, including cytokines, growth factors and chemokines. Since the molecular and cellular biology of MDSCs have been reviewed elsewhere [5], [6], [7], this review will focus on the turnover and trafficking of MDSCs in vivo from hematological and anatomical viewpoints.
Section snippets
Immunophenotype of MDSC subpopulations in mice
Immunophenotyping has been used to characterize MDSCs in tumor-bearing mice and in patients with cancer. Mouse MDSCs have been characterized as CD11b+Gr-1+ cells composed of PMNs, MOs/Mϕs, DCs and early myeloid precursors. Since the heterogeneity of the MDSC subpopulation often makes it difficult to interpret MDSC dynamics, we begin by characterizing mouse MDSC subpopulations into hematological classification according to their immunophenotype and cell morphology. The functional properties of
Origin and development of MDSC subpopulations
With the exception of tissue-resident cells such as brain microglia and epidermal Langerhans cells, which are locally maintained under steady-state conditions, PMNs, MOs/Mϕs and DCs in peripheral tissues develop from myeloid progenitors by a process called myelopoiesis. Development of PMNs or MOs specifically is referred to as granulopoiesis or monopoiesis, respectively. In this section, we discuss the developmental pathways of myeloid cells in bone marrow under steady-state conditions, and
Migration of MDSC subpopulations in the tumor-bearing host
Following functional maturation, PMNs and MOs egress from bone marrow by intravasation through the sinus endothelium to enter the systemic circulation. Circulating PMNs and MOs migrate from blood to tissues through vessels with or without specific molecular regulation. For example, open blood vessels in the red pulp and marginal zone are the site of leukocyte entry into spleen, whereas leukocyte extravasation, a sequential step mediated by lipid mediators, adhesion molecules and chemokines,
Conclusion
We have reviewed the literature with the aim of integrating recent findings on the molecular and cellular biology of MDSCs with classical understanding of hematological and anatomical principles in vivo. Recent characterization of myeloid cell subpopulations and their progenitors has led to elucidation of detailed myeloid cell developmental pathways under steady-state conditions. However, the full impact of cancer on myeloid cell dynamics remains unclear. The cell lineages, in vivo development,
Acknowledgments
We thank Drs. S. Hashimoto, K. Kakimi, M. Kurachi and J. Abe for scientific discussions. This work was partially supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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