Abstract
Highly phagocytic macrophages line the marginal zone (MZ) of the spleen and the lymph node subcapsular sinus. Although these macrophages have been attributed with a variety of functions, including the uptake and clearance of blood and lymph-borne pathogens, little is known about the effector mechanisms they employ after pathogen uptake. Here, we have combined gene expression profiling and RNAi using a stromal macrophage cell line with in situ analysis of the leishmanicidal activity of marginal zone macrophages (MZM) and marginal metallophilic macrophages (MMM) in wild type and gene targeted mice. Our data demonstrate a critical role for interferon regulatory factor-7 (IRF-7) in regulating the killing of intracellular Leishmania donovani by these specialised splenic macrophage sub-populations. This study, therefore, identifies a new role for IRF-7 as a regulator of innate microbicidal activity against this, and perhaps other, non-viral intracellular pathogens. This study also highlights the importance of selecting appropriate macrophage populations when studying pathogen interactions with this functionally diverse lineage of cells.
Highlights
Mononuclear phagocytes are widely distributed in all tissues, and provide a broad range of homeostatic and immune functions during development and throughout adult life
It has long been recognised that macrophages in different tissues look and behave differently, this heterogeneity is rarely taken into account when examining macrophage-pathogen interactions
By comparing gene expression profiles of different types of macrophages, we show here the diversity of the macrophage response to Leishmania donovani infection
Summary
Mononuclear phagocytes are widely distributed in all tissues, and provide a broad range of homeostatic and immune functions during development and throughout adult life. The heterogeneity of mature tissue macrophages represents one of the most striking, yet under-studied, features of mononuclear cell differentiation. Expression of a range of transcription factors and cellular receptors has helped define membership of the mononuclear phagocyte system [1,2,3], and whereas some tissue macrophages have a capacity for local self-renewal, others are derived from blood-borne monocytes undergoing tissue-specific differentiation [reviewed in [4]]. Readily distinguishable populations of macrophages are found in the splenic MZ, red pulp, B cell follicles and white pulp [5]. Mice lacking various transcription factors (e.g. relb and NFkB2), TNF superfamily cytokines (e.g. LTa), and chemokines (e.g. CCL19/ 21ser) exhibit steady-state defects in MZ macrophage differentiation and/or positioning [11,12], illustrating the complexity behind this micro-anatomical organisation
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