Blood Monocytes Consist of Two Principal Subsets with Distinct Migratory Properties

Geissmann, Frédéric; Jung, Steffen; Littman, Dan R.

doi:10.1016/s1074-7613(03)00174-2

Cited by 2,967 publications

(3,388 citation statements)

References 48 publications

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“…It has recently been shown that murine monocytes can be separated into 2 different populations by the presence or absence of surface marker Gr-1 (Ly6C/G) (19,20). The results of the present study showed that staining with the CCR2 mAb MC-21 selectively identified the subpopulation of Gr-1ϩ monocytes in the peripheral blood and spleen tissue from DBA/1 mice ( Figure 1A).…”

Section: Resultssupporting

confidence: 66%

Targeting of Gr‐1+,CCR2+ monocytes in collagen‐induced arthritis

Brühl¹,

Cihak²,

Plachý

et al. 2007

Arthritis & Rheumatism

108

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Objective. The chemokine receptor CCR2 is highly expressed on monocytes and considered a promising target for treatment of rheumatoid arthritis. However, blockade of CCR2 with a monoclonal antibody (mAb) during progression of collagen-induced arthritis results in a massive aggravation of the disease. In this study we investigated why CCR2 antibodies have proinflammatory effects, how these effects can be avoided, and whether CCR2؉ monocytes are useful targets in the treatment of arthritis.Methods. Arthritis was induced in DBA/1 mice by immunization with type II collagen. Mice were treated with mAb against CCR2 (MC-21), IgE, or isotype control antibodies at various time points. Activation of basophils and depletion of monocyte subsets were determined by fluorescence-activated cell sorter analysis and enzyme-linked immunosorbent assay.Results. Crosslinkage of CCR2 activated basophils to release interleukin-6 (IL-6) and IL-4. In vivo, IL-6 release occurred only after exposure to high doses of MC-21, whereas application of low doses of the mAb circumvented the release of IL-6. Regardless of the dose level used, the antibody MC-21 efficiently depleted Gr-1؉,CCR2؉ monocytes from the synovial tissue, peripheral blood, and spleen of DBA/1 mice. Activation of basophils with high doses of MC-21 or with antibodies against IgE resulted in a marked aggravation of collagen-induced arthritis and an increased release of IL-6. In contrast, low-dose treatment with MC-21 in this therapeutic setting had no effect on IL-6 and led to marked improvement of arthritis.Conclusion. These results show that depletion of CCR2؉ monocytes may prove to be a therapeutic option in inflammatory arthritis, as long as the dosedependent proinflammatory effects of CCR2 mAb are taken into account.CCR2, a chemokine (CC motif) receptor, is considered a promising target for disorders such as multiple sclerosis, type II diabetes, and rheumatoid arthritis, and Phase I and II clinical trials are currently in progress (1). Data on CCR2 expression in humans and results from studies of CCR2-deficient mice (2-4) support the blockade of CCR2 as an effective strategy in the treatment of multiple sclerosis and diabetes. In patients with rheumatoid arthritis, we and other investigators have found an increased frequency of CCR2ϩ cells in the synovial fluid and synovial tissue (5-7). In addition, increased levels of the CCR2 ligand monocyte chemoattractant protein 1 (MCP-1; CCL2) were found in patients with rheumatoid arthritis (8). Monocytes are thought to play a major role in joint destruction, and their recruitment to sites of inflammation is crucially dependent on CCR2, as shown in several murine disease models (9-12).However, thus far, data from murine models of collagen-induced arthritis do not support CCR2 as a target for treatment of rheumatoid arthritis. We have previously shown that treatment with a blocking monoDrs. Brühl, Luckow,

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Section: Resultssupporting

confidence: 66%

Targeting of Gr‐1+,CCR2+ monocytes in collagen‐induced arthritis

Brühl¹,

Cihak²,

Plachý

et al. 2007

Arthritis & Rheumatism

108

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“…CX3CR1À/À mice were reported to have a significant reduction in macrophage recruitment to the vessel wall and decreased atherosclerotic lesion formation (Lesnik et al, 2003). Others found that the CX3CR1 high CCR À 2Gr À subset of murine blood monocytes is characterized by CX3CR1-dependent recruitment to noninflamed tissues and that a shortlived CX3CR1 low CCR2 À Gr1 À cell population is actively recruited to inflamed tissue (Geissmann et al, 2003). We observed a lower number of GFP + /CD45 + microglia/macrophages in the ipsilateral cerebral cortex of CX3CR1 + /À mice at 72 h, possibly as a result of more serious ischemia and decreased microglial proliferation (Denes et al, 2007) and/or recruitment.…”

Section: Discussionmentioning

confidence: 99%

Role of CX3CR1 (Fractalkine Receptor) in Brain Damage and Inflammation Induced by Focal Cerebral Ischemia in Mouse

Dénes

Ferenczi

Halász

et al. 2008

J Cereb Blood Flow Metab

249

220

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CX3CR1 (fractalkine receptor) is important for sustaining normal microglial activity in the brain. Lack of CX3CR1 reportedly results in neurotoxic microglial phenotype in disease models. The objective of this study was to test the hypothesis that the absence of CX3CR1 worsens the outcome in cerebral ischemia. We observed significantly smaller (56%) infarcts and blood-brain barrier damage in CX3CR1-deficient (CX3CR1À/À) animals compared with CX3CR1 + /À and wild-type mice after transient occlusion of the middle cerebral artery (MCAo). Functional recovery of CX3CR1À/À animals was enhanced, while less number of apoptotic cells and infiltrating leukocytes were found in the ipsilateral hemisphere. Expression of IL-1b mRNA, protein, and interleukin (IL)-1Ra and tumor necrosis factor (TNF)-a mRNAs was lower in CX3CR1À/À mice, whereas no difference was observed in the number of IL-1b-expressing microglia or plasma IL-1b concentration. We observed early IL-1b expression in astrocytes in vivo after MCAo and after oxygen-glucose deprivation in vitro, which might contribute to the ischemic damage. Our findings indicate that lack of CX3CR1 does not result in microglial neurotoxicity after MCAo, but rather significantly reduces ischemic damage and inflammation. Reduced IL-1b and TNFa expression as well as decreased leukocyte infiltration might be involved in the development of smaller infarcts in CX3CR1À/À animals.

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“…As the major monocyte population in normal blood in humans, CD14 hi CD16 − defines 'classical' or inflammatory monocytes [71]. In mice, this population is identified by its Ly6C hi CD43 lo CCR2+ CX3CR1 lo phenotype [72,73]. By contrast, a much smaller, CD14 lo , CD16 hi 'nonclassical' or patrolling monocyte subset comprises some 10% of blood monocytes in humans and is defined as Ly6C lo CD43 hi CCR2 lo CX3CR1 hi in mice [72,73].…”

Section: Targeting Inflammatory Myeloid Cellsmentioning

confidence: 99%

“…In mice, this population is identified by its Ly6C hi CD43 lo CCR2+ CX3CR1 lo phenotype [72,73]. By contrast, a much smaller, CD14 lo , CD16 hi 'nonclassical' or patrolling monocyte subset comprises some 10% of blood monocytes in humans and is defined as Ly6C lo CD43 hi CCR2 lo CX3CR1 hi in mice [72,73]. CD14 hi CD16 hi and Ly6C hi CD43 hi subsets define an intermediate group in humans and mice, respectively.…”

Section: Targeting Inflammatory Myeloid Cellsmentioning

confidence: 99%

Harnessing Nanoparticles for Immune Modulation

Getts¹,

Shea²,

Miller³

et al. 2016

Trends in Immunology

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Recent approaches using nanoparticles engineered for immune regulation have yielded promising results in preclinical models of disease. The number of nanoparticle therapies is growing, fueled by innovations in nanotechnology and advances in understanding of the underlying pathogenesis of immune-mediated diseases. In particular, recent mechanistic insight into the ways in which nanoparticles interact with the mononuclear phagocyte system and impact its function during homeostasis and inflammation have highlighted the potential of nanoparticle-based therapies for controlling severe inflammation while concurrently restoring peripheral immune tolerance in autoimmune disease. Here we review recent advances in nanoparticle-based approaches aimed at immune-modulation, and discuss these in the context of concepts in polymeric nanoparticle development, including particle modification, delivery and the factors associated with successful clinical deployment.

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Blood Monocytes Consist of Two Principal Subsets with Distinct Migratory Properties

Cited by 2,967 publications

References 48 publications

Targeting of Gr‐1+,CCR2+ monocytes in collagen‐induced arthritis

Targeting of Gr‐1+,CCR2+ monocytes in collagen‐induced arthritis

Role of CX3CR1 (Fractalkine Receptor) in Brain Damage and Inflammation Induced by Focal Cerebral Ischemia in Mouse

Harnessing Nanoparticles for Immune Modulation

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