Article

Minimal Differentiation of Classical Monocytes as They Survey Steady-State Tissues and Transport Antigen to Lymph Nodes

Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Immunity (Impact Factor: 21.56). 09/2013; 39(3). DOI: 10.1016/j.immuni.2013.08.007
Source: PubMed

ABSTRACT

It is thought that monocytes rapidly differentiate to macrophages or dendritic cells (DCs) upon leaving blood. Here we have shown that Ly-6C(+) monocytes constitutively trafficked into skin, lung, and lymph nodes (LNs). Entry was unaffected in gnotobiotic mice. Monocytes in resting lung and LN had similar gene expression profiles to blood monocytes but elevated transcripts of a limited number of genes including cyclo-oxygenase-2 (COX-2) and major histocompatibility complex class II (MHCII), induced by monocyte interaction with endothelium. Parabiosis, bromodoxyuridine (BrdU) pulse-chase analysis, and intranasal instillation of tracers indicated that instead of contributing to resident macrophages in the lung, recruited endogenous monocytes acquired antigen for carriage to draining LNs, a function redundant with DCs though differentiation to DCs did not occur. Thus, monocytes can enter steady-state nonlymphoid organs and recirculate to LNs without differentiation to macrophages or DCs, revising a long-held view that monocytes become tissue-resident macrophages by default.

Download full-text

Full-text

Available from: Claudia Jakubzick, Aug 27, 2015
  • Source
    • "The reduction of these cells in the spleen could be due to either maturation-induced cell death or migration, or a phenotypic alteration of the cells (Asselin-Paturel et al., 2005; Swirski et al., 2009). Although not quantified as a separate population here, the percentage of transitional Ly6C + MHCII + cells increased as expected because immune activation triggers the differentiation of Ly6C + MHCII − cells to Ly6C − MHCII + cells (Jakubzick et al., 2013). Cells within gate 2 displayed fewer changes with CpG but, a significant increase in the percentage of CD8 + cDC1s was detected (Fig 3). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of antigen presenting cells (APCs) in the pathogenesis of autoimmune- and other inflammatory diseases is now better understood due to advances in multicolor flow cytometry, gene expression analysis of APC populations, and functional correlation of mouse to human APC populations. A simple but informative nomenclature of conventional and plasmacytoid dendritic cell subsets (cDC1, cDC2, pDC) and monocyte-derived populations incorporates these advances, but accurate subset identification is critical. Ambiguous gating schemes and alterations of cell surface markers in inflammatory condition can make comparing results between studies difficult. Both acute inflammation, such as TLR-ligand stimulation, and chronic inflammation as found in mouse models of autoimmunity can alter DC subset gating. Here, we address these issues using in vivo CpG stimulation as an example of acute inflammation and the non-obese diabetic (NOD) mouse as a model of chronic inflammation.We provide a flow cytometric antibody panel and gating scheme that differentiate 2 monocytic and 3 DC subsets in the spleen both at steady state and after CpG stimulation. Using this method, we observed differences in the composition of NOD DCs that have been previously reported, and newly identified increases in the number of NOD monocyte-derived DCs. Finally, we established a protocol for DC phosphoflow to measure the phosphorylation state of intracellular proteins, and use it to confirm functional differences in the identified subsets. Therefore, we present optimized methods for distinguishing monocytic and DC populations with and without inflammation and/or autoimmunity associated with NOD mice.
    Full-text · Article · Sep 2015 · Journal of immunological methods
  • Source
    • "A recent review by Hussell and Bell provides an updated overview of the mechanisms of AM negative regulation [77]. Intestinal macrophages, as all tissue macrophages, also serve as antigen-presenting cells in triggering adaptive immune responses at the tissue level, and they can also contribute to T cell priming (through the so-called " tissue monocytes " that are able to recirculate to the lymph nodes [78]). In this regard, it is now believed that mucosal macrophages are able to transfer luminal antigens to neighboring CD103 + DCs through the gap junction channel protein connexin 43 [79]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The epithelial layers that line the human gut and airways have evolved into tightly regulated mechanical and functional tissue barriers, the mucosae, which have to cope with unrelenting exposure to food-and airborne contaminants. In these barriers, immune cells play a major defensive role. This review describes the most important cellular and molecular mechanisms of mucosal leukocytes during homeostasis and physiological inflammation with a major focus on innate immunity (i.e. the immediate response against potential invaders). In homeostasis, a well-defined mucus layer and the epithelial layer hinder microbes from entering the underlying tissue. In addition, mucosal macrophages are patrolling scavengers with high phagocytic capacity, but their ability to mount an inflammatory response is down-regulated. Innate lymphoid cells also have an important role in maintaining a healthy mucosa. However, if bacteria overcome the barrier they cause an inflammatory reaction aimed at eliminating the threat and re-establishing tissue homeostasis. During the inflammatory response, tissue-resident immune cells become activated and promote the recruitment of monocytes and other leukocytes from the blood to the site of inflammation. The reaction evolves the contribution of mononuclear phagocytes, mast cells, neutrophils and ILCs until the infection is eliminated, tissue damage repaired and homeostasis re-established.
    Full-text · Article · Dec 2014
  • Source
    • "However, in the absence of CCR2, Ly6C + monocytes can give rise to Ly6C + CD64 int cells, which may differentiate into macrophages. The Ly6C + CD64 int cells are not depleted after the systemic administration of clodronate-loaded liposomes, suggesting these cells may originate from extravasated tissuesurveying monocytes (Jakubzick et al., 2013). Recently, macrophage polarization in health and disease has received a great deal of attention due to the therapeutic potential of altering macrophage phenotype. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Different subsets and/or polarized phenotypes of monocytes and macrophages may play distinct roles during the development and resolution of inflammation. Here, we demonstrate in a murine model of rheumatoid arthritis that nonclassical Ly6C(-) monocytes are required for the initiation and progression of sterile joint inflammation. Moreover, nonclassical Ly6C(-) monocytes differentiate into inflammatory macrophages (M1), which drive disease pathogenesis and display plasticity during the resolution phase. During the development of arthritis, these cells polarize toward an alternatively activated phenotype (M2), promoting the resolution of joint inflammation. The influx of Ly6C(-) monocytes and their subsequent classical and then alternative activation occurs without changes in synovial tissue-resident macrophages, which express markers of M2 polarization throughout the course of the arthritis and attenuate joint inflammation during the initiation phase. These data suggest that circulating Ly6C(-) monocytes recruited to the joint upon injury orchestrate the development and resolution of autoimmune joint inflammation.
    Full-text · Article · Oct 2014 · Cell Reports
Show more