Fate Mapping Reveals Origins and Dynamics of Monocytes and Tissue Macrophages under Homeostasis

Yona, Simon; Kim, Ki Wook; Wolf, Yochai; Mildner, Alexander; Varol, Diana; Breker, Michal; Strauss-Ayali, Dalit; Viukov, Sergey; Guilliams, Martin; Misharin, Alexander V.; Hume, David; Perlman, Harris; Malissen, Bernard; Zelzer, Elazar; Jung, Steffen

doi:10.1016/j.immuni.2012.12.001

Cited by 2,535 publications

(2,429 citation statements)

References 69 publications

Supporting

Mentioning

2,324

Contrasting

Unclassified

Order By: Relevance

“…The Gr-1 ϩ , myeloperoxidase-negative Ly-6C ϩ cells that entered infected lungs, took up MCMV antigens, and became infected corresponded to inflammatory monocytes, (52). These cells were interstitial, whereas Gr-1 Ϫ Ly-6C-negative AMs were in the airspaces.…”

Section: Discussionmentioning

confidence: 99%

Alveolar Macrophages Are a Prominent but Nonessential Target for Murine Cytomegalovirus Infecting the Lungs

Farrell

Lawler

Oliveira

et al. 2016

J Virol

View full text Add to dashboard Cite

H erpesviruses are among the most prevalent of all mammalian pathogens. Many cause lung disease (1-5), making the lung an important site of infection. Human cytomegalovirus (HCMV) causes interstitial pneumonitis in immunocompromised patients (5). While HCMV could potentially reach the lungs via circulating monocytes (6), viral lytic antigen expression in alveolar epithelial cells (AECs) (7-9) and alveolar macrophage (AM) infection (10) suggest entry by inhalation.Sporadic transmission and late clinical presentation make early HCMV infection hard to analyze. However, the relatedness between cytomegaloviruses (CMVs) and their hosts implies that CMV parasitism preceded the speciation of most mammals (11), and peaks of viral diversity in genes engaging the immune functions of diverse hosts suggest that coevolution has operated since to conserve a parasitic status quo. Therefore, nonhuman CMVs can help us to understand how HCMV works. The preeminence of mice as experimental models of mammalian cell biology gives murine CMV (MCMV) particular value in this regard. It causes an interstitial pneumonitis after intranasal (i.n.) inoculation, infecting epithelial and mononuclear cells (12). Thus, it reproduces at least some features of HCMV lung infection.Which lung cells CMVs infect first is unknown. The ciliated upper airways capture large inhaled particles (diameter, Ͼ5 m), but submicron-sized particles, such as viruses, can reach the lung alveoli (13). Here, type 1 alveolar epithelial cells (AEC1s) provide Ͼ90% of the accessible surface, their abundant type 2 progenitors (AEC2s) produce surfactant, and AMs patrol the airspaces for inhaled pathogens. In neonatal mice, i.n. inoculated MCMV infects AMs and AEC2s (14). Infection was reduced when AMs were depleted with liposomal clodronate or when MCMV lacked m129 (15). The m131/m129 MCMV chemokine homolog (designated MCK2) attracts macrophages (16) and alters viral tropism to promote macrophage infection (17). Thus, it was concluded that AMs provide an acutely productive gateway into the lungs. However, MCK2-negative (MCK2 Ϫ ) MCMV given intra-

show abstract

Section: Discussionmentioning

confidence: 99%

Alveolar Macrophages Are a Prominent but Nonessential Target for Murine Cytomegalovirus Infecting the Lungs

Farrell

Lawler

Oliveira

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…When the mature cells enter the peripheral blood, they are termed monocytes (Figure 2). The monocytes often leave the blood and infiltrate tissues, undergoing additional changes and are then referred to as macrophages [40]. Macrophages act as effector cells, attacking microorganisms and neoplastic cells and removing foreign material, as well as presenting antigen + stem cells.…”

Section: Cells Of the Monocyte-macrophage Lineagementioning

confidence: 99%

Myelomonocytic Cell Lines in Modeling HIV-1 Infection of the Bone Marrow

Nonnemacher¹,

Quiterio²,

Allen³

et al. 2017

Biology of Myelomonocytic Cells

View full text Add to dashboard Cite

Human immunodeficiency virus type 1 (HIV-1), the etiologic agent of acquired immunodeficiency syndrome (AIDS), primarily infects T cells and cells of the monocyte-macrophage lineage. This is due to the presence of the cell surface receptor CD4 and the coreceptors, CXCR4, and CCR5. While the T-cell has classically been the cell type associated with HIV-1 disease progression, cells of the monocyte-macrophage lineage have also been shown to play a major role in this viral pathologic process. Classically, this has involved monocytic cells in the peripheral blood and tissue macrophages, however, over the course of HIV disease, the promyelomonocytic cells of the bone marrow (BM) have also been shown to play a role in pathogenesis retroviral disease in that they play an integral role in the reseeding of the periphery and end-organ tissues. This has involved an initial infection of the bone marrow hematopoietic progenitor cells. Given this observation, over the years there have been a number of cell lines that have been developed and provided valuable insights into research questions surrounding HIV-1 infection of the monocyte-macrophage cell lineage. In this regard, we will examine the biological and immunological properties of these BM-derived cell lines with respect to their utility in exploring the pathogenesis of HIV-1 in humans.

show abstract

“…5). These results not only show that microglia actively clear away myelin, but also indicate that this process is associated with the accumulation of undegradable lysosomal aggregates in microglia of the aging brain.Given that microglia appear to be involved in myelin clearance, we reasoned that blocking lysosomal degradation should lead to the accumulation of myelin fragments in younger mice.Thus, we generated conditional Rab7 KO mice using CX 3 CR1 CreER animals to specifically interfere with lysosomal function in microglia/macrophage 16,17 . Cell-specific recombination was confirmed by crossing mice with TdTomato reporter line, which showed TdTomato expression in more than 90% of the microglia (Supplementary Fig.…”

mentioning

confidence: 99%

“…Thus, we generated conditional Rab7 KO mice using CX 3 CR1 CreER animals to specifically interfere with lysosomal function in microglia/macrophage 16,17 . Cell-specific recombination was confirmed by crossing mice with TdTomato reporter line, which showed TdTomato expression in more than 90% of the microglia (Supplementary Fig.…”

mentioning

confidence: 99%

Age-related myelin degradation burdens the clearance function of microglia during aging

Kannaiyan²,

et al. 2016

Self Cite

View full text Add to dashboard Cite

2Myelin is synthesized as a multilamellar membrane, but the mechanisms of membrane turnover are unknown. We find that myelin pieces are gradually released from aging myelin sheaths and are subsequently cleared by microglia. Myelin fragmentation increases with age and leads to the formation of insoluble, lipofuscin-like lysosomal inclusions in microglia. Thus, age-related myelin fragmentation is substantial leading to lysosomal storage and contributing to microglia senescence and immune dysfunction in aging.Myelin is formed by oligodendrocytes as a multilamellar structure that encloses segments of axons in the central nervous systems (CNS) of vertebrates 1 . Once myelin is laid down, it is unknown to what extent the sheaths require maintenance and remodeling. Membrane turnover may pose a problem for oligodendrocytes that form up to 80 different myelin sheaths of tightly stacked membrane, but harbour little cytoplasm and few lysosomes, the organelles responsible for membrane degradation. Myelin membrane components are metabolically relatively stable with half-lives on the order of several weeks to months 2,3 . Nevertheless, protein/lipid turnover is, in general, necessary to replace potentially impaired molecules with new functional copies in order to combat functional decline [4][5][6][7] . How do molecules trapped within the numerous layers of tightly compacted membrane enter the degradative system? We tested the hypothesis that myelin degradation occurs in part via shedding of myelin fragments into the extracellular space.We analyzed the white matter of aging mice (up to 24 months) by electron microscopy to search for myelin breakdown products. We detected multilamellar myelin fragments more frequently in the brain of the older mice, of which some were associated with myelin sheaths, while others were in the extracellular space or inside of cells (Supplementary Fig. 1). As fixation artefacts frequently affect the appearance of myelin in chemically fixed tissue, we used high-pressure freezing to fix tissue and confirmed the progressive accumulation of multilamellar myelin fragments with age ( Fig. 1a,b).Since some of these myelin fragments were found inside cells, we performed immunhistochemistry to determine whether microglia, the brain phagocytes [8][9][10] , were responsible for the uptake of myelin fragments. An increasing number of myelin basic protein (MBP) and proteolipid protein (PLP) immunoreactive puncta co-localized with Iba1-positive microglia with age ( Fig. 1c, Supplementary Fig. 1).Three-dimensional reconstructions demonstrated that immunoreactive puncta were present inside of microglia (Fig. 1c). Since our results suggested that microglia clear away the myelin fragments that accumulate in the 3 aging brain, we compared microglia number and appearance in young and old animals. Not only had the number of microglia increased in the white matter of old animals as reported previously 11,12 , but also microglia in contact with myelin ( Supplementary Fig. 2). Next, the morphology of lysosomes was evalua...

show abstract

Fate Mapping Reveals Origins and Dynamics of Monocytes and Tissue Macrophages under Homeostasis

Cited by 2,535 publications

References 69 publications

Alveolar Macrophages Are a Prominent but Nonessential Target for Murine Cytomegalovirus Infecting the Lungs

Alveolar Macrophages Are a Prominent but Nonessential Target for Murine Cytomegalovirus Infecting the Lungs

Myelomonocytic Cell Lines in Modeling HIV-1 Infection of the Bone Marrow

Age-related myelin degradation burdens the clearance function of microglia during aging

Contact Info

Product

Resources

About