Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-β signaling
Harald LundMelanie PieberRoham ParsaDavid GrommischEwoud EwingLara KularJinming HanKeying ZhuJik NijssenEva HedlundMaria NeedhamsenStephan RuhrmannAndré Ortlieb Guerreiro‐CacaisRasmus BerglundMaría J. FortezaDaniel F.J. KetelhuthOleg ButovskyMaja JagodicXing‐Mei ZhangRobert A. Harris
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Monocyte
CX3CR1
Demyelinating disease
The studies on fractalkine and its unique receptor CX3CR1 in neurological disorders yielded contrasting results. We have explored the consequences of CX3CR1 deletion in ischemic (30′ MCAo) mice on: (1) brain infarct size; (2) microglia dynamism and morphology; (3) expression of markers of microglia/macrophages (M/M) activation and polarization. We observed smaller infarcts in cx3cr1 −/− (26.42 ± 7.41 mm 3 , mean ± sd) compared to wild type (36.29 ± 11.57) and cx3cr1 −/+ (34.49 ± 8.91) mice. We longitudinally analyzed microglia by in vivo two‐photon microscopy before, 1 and 24 h after transient ischemia. Microglia were stationary in both cx3cr1 −/− and cx3cr1 −/+ mice throughout the study. In cx3cr1 −/− mice, they displayed a significantly higher number of ramifications >10 μm at baseline and at 24 h after ischemia compared to cx3cr1 −/+ mice, indicating that CX3CR1 deficiency impaired the development of microglia hypertrophic/amoeboid morphology. At 24 h after ischemia, we performed post mortem quantitative immunohistochemistry for different M/M markers. In cx3cr1 −/− immunoreactivity for CD11b (M/M activation) and for CD68 (associated with phagocytosis) were decreased, while that for CD45 high (macrophage and leukocyte recruitment) was increased. In addition, immunoreactivity for Ym1 (M2 polarization) was enhanced, while that for iNOS (M1) was decreased. Our data show that in cx3cr1 −/− mice protection from ischemia at early time points after injury is associated with a protective inflammatory milieu, characterized by the promotion of M2 polarization markers.
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Objective To explore the effect of corticotropin-releasing hormone(CRH) on phagocytosis of rat enterocoelia macrophage.Methods The chicken-red cells were added in the media of rat enterocoelia macrophage cultivated by CRH after 1、2、4、8、16 hours.Then the effect of CRH on phagocytosis of rat enterocoelia macrophage was evaluated by the chicken-red cells phagocytosis index and phagocytosis rate.Results Comparing with the control groups,the phagocytosis index and phagocytosis rate of experimental groups both improved significantly in each time point(P0.05).Among the experimental groups,the phagocytosis index and phagocytosis rate were the highest and the phagocytosis was at the top in the 2 hours group.Conclusion CRH could markedly improve the phagocytosis of rat enterocoelia macrophage.
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Neuropathic pain (NP) is a serious problem caused by lesions or diseases in the peripheral or central nervous system. It has been widely known that various immune cells contribute to the development and maintenance of NP, and thus the importance of spinal microglia in pain formation. To more specifically evaluate the role of microglia on pain regulation and its sex-dependency, we used Gi or Gq-Designer Receptors Exclusively Activated by Designer Drugs（Gi/Gq-DREADD）system driven by microglia-specific cx3cr1 promoter in both male and female mice (indicated as CX3CR1-hM4Di or CX3CR1-hM3Dq mice, respectively). In CX3CR1-hM4Di or CX3CR1-hM3Dq mice, expression of hM4Di or hM3Dq was detected in Iba1-positive microglia, but not in astrocytes or neurons. Intraperitoneal (i.p.) or intrathecal (i.t.) administration of clozapine-N-oxide (CNO), a ligand for hM4Di and hM3Dq, attenuated mechanical allodynia, evaluated by von Frey test, in CX3CR1-hM4Di mouse models of NP. While, either i.p. or i.t. administration of CNO induced mechanical allodynia in CX3CR1-hM3Dq mice. More importantly, these effects on pain regulation in CX3CR1-hM4Di and CX3CR1-hM3Dq mice were only observed in male, but not in female mice. These findings support the notion that sex-dependent pain-regulatory effects of spinal microglia in mice.
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We analysed kinetics of phagocytosis by using the whole blood and fluorescent microspheres with flow cytometry. The rate of phagocytosis (y) was determined by the T/C (target particles-to-cell) ratio (x) (y=K1×log (x) +K2 K1, K2: constant) . We defined the Phagocytosis 50 (Ph 50) that indicated the value of T/C ratio in which 50% of phagocytes injested the particles. The Ph 50 might be the new general parameter of phagocytosis independent of several conditions.The Ph 50 in cases of systemic lupus erythematosus (SLE) were statistically higher than in normal controls, which indicated the decreased phagocytic activity in SLE.
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The effect of phagocytosis-stimulating factor (PSF) on phagocytosis was studied in detail. PSF did not affect the Fc receptor-mediated phagocytosis, whereas PSF enhanced the ingestion step, but not attachment step, of C3b receptor-mediated phagocytosis by polymorphonuclear neutrophils (PMNs), suggesting that PSF may specifically modulate the C3b receptor function of PMNs. PSF generated from guinea pig PMNs enhanced phagocytosis by rabbit PMNs, and rabbit PMN-produced PSF accelerated the phagocytosis by guinea pig PMNs, indicating that PSF is not specific for animal species. The effects of PSF on some PMN functions, such as O2- generation, chemotaxis, adherence, and enzyme release, were also studied. Only O2- generation from PMNs was significantly increased in the initial phase of phagocytosis, and this stimulation of O2- generation was completely parallel with the stimulation of phagocytosis by PSF. Resting PMNs hardly generated the superoxide anions by PSF treatment, suggesting that PSF does not affect the O2- forming system directly.
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ABSTRACT We have studied the ability of human polymorphonuclear leukocytes (PMN) to phagocytose Capnocytophaga ochracea in three-dimensional fibrin meshworks. Phagocytosis was assessed in three systems: (1) the PMN and bacteria were mixed together with plasma and clotted; 60±13% phagocytosis occurred after 60 min; (2) PMN were overlaid on clots containing bacteria; the PMN migrated into the clot and after 60 min 52±7% phagocytosis was seen; (3) PMN had to migrate from within one clot into a second containing bacteria; phagocytosis after 60 min was 54±3 %. In the clots, PMN released lysozyme but this was not significantly enhanced by phagocytosis. These findings indicate that PMN are capable of phagocytosing in each of the threedimensional systems tested and that they are capable of both migration into and subsequent phagocytosis in a model that more closely mimics the in vivo structure in which PMN would normally perform.
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Generation of a Phagocytosis-Stimulating Factor by Polymorphonuclear Neutrophils during Phagocytosis
Polymorphonuclear neutrophils (PMNs) generated a phagocytosis-stimulating factor (PSF) intracellularly during phagocytosis of opsonized zymosan or latex particles. The generation of PSF by PMNs reached the maximum at 60 min after the start of phagocytosis. When PSF was washed out after preincubation with PMNs or opsonized zymosan particles, no enhancement of phagocytosis by PMNs was observed, suggesting that the continuous existence of PSF in the incubation medium is required for stimulation of phagocytosis.
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