Tissue-Resident Macrophages Self-Maintain Locally throughout Adult Life with Minimal Contribution from Circulating Monocytes

Hashimoto, Daigo; Chow, Andrew; Noizat, Clara; Teo, Pearline; Beasley, Mary Beth; Leboeuf, Marylène; Becker, Christian; See, Peter; Price, Jeremy; Lucas, Daniel; Greter, Melanie; Mortha, Arthur; Boyer, Scott W.; Forsberg, Erik; Tanaka, Masato; Rooijen, Nico van; García‐Sastre, Adolfo; Stanley, E. Richard; Ginhoux, Florent; Frenette, Paul S.; Mérad, Miriam

doi:10.1016/j.immuni.2013.04.004

Cited by 1,787 publications

(1,805 citation statements)

References 46 publications

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“…89,90 Alternatively, emerging studies support the notion of parenchymal macrophage repopulation in tissues and not from bone marrow, which is an interesting field of future study that may, in part, account for a lack of BrdU þ CD163 macrophages in parenchymal lesions in our study. 91,92 The Presence of CD163 þ BrdU þ Macrophages in the Meninges and Choroid Plexus Underscores Differences between CNS Compartments and a Possible Route of Viral Entry into the CNS Given that we did not observe CD163 þ BrdU þ macrophages in the perivascular space and SIVE lesions, it is interesting that we observed CD163 þ BrdU þ macrophages in the meninges and choroid plexus in numbers equal to or greater than MAC387 þ BrdU þ macrophages. This observation suggests that these two compartments are more similar to each other, and possibly to blood, than to the perivascular space and CNS parenchyma.…”

Section: Mac387 þ Macrophages Do Not Appear To Differentiate Into Cd1mentioning

confidence: 89%

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

Nowlin

Burdo

Midkiff

et al. 2015

The American Journal of Pathology

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Macrophage recruitment to the central nervous system (CNS) during AIDS pathogenesis is poorly understood. We measured the accumulation of brain perivascular (CD163 þ ) and inflammatory (MAC387 þ ) macrophages in SIV-infected monkeys. Monocyte progenitors were 5-bromo-2 0 -deoxyuridine (BrdU) labeled in bone marrow, and CNS macrophages were labeled serially with fluorescent dextrans injected into the cisterna magna. MAC387 þ macrophages accumulated in the meninges and choroid plexus in early inflammation and in the perivascular space and SIV encephalitis (SIVE) lesions late. CD163 þ macrophages accumulated in the perivascular space and SIVE lesions with late inflammation. Most of the BrdU þ cells were MAC387 þ ; however, CD163 þ BrdU þ macrophages were present in the meninges and choroid plexus with AIDS. Most (81.6% AE 1.8%) of macrophages in SIVE lesions were present in the CNS before SIVE lesion formation. There was a 2.9-fold increase in SIVp28 þ macrophages entering the CNS late compared with those entering early (P < 0.05). The rate of CD163 þ macrophage recruitment to the CNS inversely correlated with time to death (P < 0.03) and increased with SIVE. In SIVE animals, soluble CD163 correlated with CD163 þ macrophage recruitment (P Z 0.02). Most perivascular macrophages that comprise SIVE lesions and multinucleated giant cells are present in the CNS early, before SIVE lesions are formed. Most SIV-infected macrophages traffic to the CNS terminally with AIDS.

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Section: Mac387 þ Macrophages Do Not Appear To Differentiate Into Cd1mentioning

confidence: 89%

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

Nowlin

Burdo

Midkiff

et al. 2015

The American Journal of Pathology

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“…For a long time, tissue macrophages are thought to be derived from circulating monocytes as donor-derived monocytes contribute to tissue macrophages following BM transplantation (31). Recently, however, accumulating evidence suggests that macrophages in many tissues, such as the brain and liver, are maintained by self-renewal, independent of circulating monocytes (24,(31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, however, accumulating evidence suggests that macrophages in many tissues, such as the brain and liver, are maintained by self-renewal, independent of circulating monocytes (24,(31)(32)(33). Following expression of human M-CSF in humanized mice, human macrophages are induced and take up residence at the same location in the liver and the lungs as the mouse macrophages.…”

Section: Discussionmentioning

confidence: 99%

Induction of Functional Human Macrophages from Bone Marrow Promonocytes by M-CSF in Humanized Mice

Chen

Zheng

et al. 2013

The Journal of Immunology

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Engraftment of human CD34+ hematopoietic stem/progenitor cells into immunodeficient mice leads to robust reconstitution of human T and B cells but not monocytes and macrophages. To identify the cause underlying the poor monocyte and macrophage reconstitution, we analyzed human myeloid cell development in humanized mice and found that it was blocked at the promonocyte stage in the bone marrow. Expression of human M-CSF or GM-CSF by hydrodynamic injection of cytokine-encoding plasmid completely abolished the accumulation of promonocytes in the bone marrow. M-CSF promoted the development of mature monocytes and tissue-resident macrophages whereas GM-CSF did not. Moreover, correlating with an increased human macrophages at the sites of infection, M-CSF–treated humanized mice exhibited an enhanced protection against influenza virus and Mycobacterium infection. Our study identifies the precise stage at which human monocyte/macrophage development is blocked in humanized mice and reveals overlapping and distinct functions of M-CSF and GM-CSF in human monocyte and macrophage development. The improved reconstitution and functionality of monocytes/macrophages in the humanized mice following M-CSF expression provide a superior in vivo system to investigate the role of macrophages in physiological and pathological processes.

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“…In addition to classical monocytederived MFs, which are recruited during inflammation, a large group of tissue-resident MFs, such as Kupffer cells, splenic MFs, alveolar MFs, and resident peritoneal MFs settle the tissues during embryogenesis. Notably, such resident MFs sustain their numbers via local proliferation throughout adulthood independent from monocyte-derived precursors (15)(16)(17). However, little is known about the differential function and specific properties of inflammatory (monocyte-derived) and resident MFs.…”

Section: Tissue-resident Mfs Perform the Noninflammatory Clearance Ofmentioning

confidence: 99%

The Nuclear Receptor Nr4a1 Mediates Anti-Inflammatory Effects of Apoptotic Cells

Ipseiz

Uderhardt

Scholtysek

et al. 2014

The Journal of Immunology

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Uptake of apoptotic cells (ACs) by macrophages ensures the nonimmunogenic clearance of dying cells, as well as the maintenance of self-tolerance to AC-derived autoantigens. Upon ingestion, ACs exert an inhibitory influence on the inflammatory signaling within the phagocyte. However, the molecular signals that mediate these immune-modulatory properties of ACs are incompletely understood. In this article, we show that the phagocytosis of apoptotic thymocytes was enhanced in tissue-resident macrophages where this process resulted in the inhibition of NF-κB signaling and repression of inflammatory cytokines, such as IL-12. In parallel, ACs induced a robust expression of a panel of immediate early genes, which included the Nr4a subfamily of nuclear receptors. Notably, deletion of Nr4a1 interfered with the anti-inflammatory effects of ACs in macrophages and restored both NF-κB signaling and IL-12 expression. Accordingly, Nr4a1 mediated the anti-inflammatory properties of ACs in vivo and was required for maintenance of self-tolerance in the murine model of pristane-induced lupus. Thus, our data point toward a key role for Nr4a1 as regulator of the immune response to ACs and of the maintenance of tolerance to “dying self.”

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Tissue-Resident Macrophages Self-Maintain Locally throughout Adult Life with Minimal Contribution from Circulating Monocytes

Cited by 1,787 publications

References 46 publications

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

Induction of Functional Human Macrophages from Bone Marrow Promonocytes by M-CSF in Humanized Mice

The Nuclear Receptor Nr4a1 Mediates Anti-Inflammatory Effects of Apoptotic Cells

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