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To determine the prevalence and clinical characteristics of patients with in Japan, we conducted a nationwide survey of primary immunodeficiency disease (PID) patients for the first time in 30 years. Questionnaires were sent to 1,224 pediatric departments and 1,670 internal medicine departments of Japanese hospitals. A total of 1,240 patients were registered. The estimated number of patients with PID was 2,900 with a prevalence of 2.3 per 100,000 people and homogenous regional distribution in Japan. The male-to-female ratio was 2.3:1 with a median age of 12.8 years. Adolescents or adults constituted 42.8% of the patients. A number of 25 (2.7%) and 78 (8.5%) patients developed malignant disorders and immune-related diseases, respectively, as complications of primary immunodeficiency disease. Close monitoring and appropriate management for these complications in addition to prevention of infectious diseases is important for improving the quality of life of PID patients.

Bacillus anthracis is the etiologic agent of the disease inhalational anthrax, an acute systemic infection initiated by inhaling spores, which if not rapidly detected and treated, results in death. Decades of research have elucidated novel aspects of anthrax pathogenesis but there are many issues left unresolved., (Published by Elsevier Masson SAS.)

Chronic systemic inflammatory conditions, such as atherosclerosis, diabetes and obesity are associated with increased risk of stroke, which suggests that systemic inflammation may contribute to the development of stroke in humans. The hypothesis that systemic inflammation may induce brain pathology can be tested in animals, and this was the key objective of the present study. First, we assessed inflammatory changes in the brain in rodent models of chronic, systemic inflammation. PET imaging revealed increased microglia activation in the brain of JCR-LA (corpulent) rats, which develop atherosclerosis and obesity, compared to the control lean strain. Immunostaining against Iba1 confirmed reactive microgliosis in these animals. An atherogenic diet in apolipoprotein E knock-out (ApoE(-/-)) mice induced microglial activation in the brain parenchyma within 8 weeks and increased expression of vascular adhesion molecules. Focal lipid deposition and neuroinflammation in periventricular and cortical areas and profound recruitment of activated myeloid phagocytes, T cells and granulocytes into the choroid plexus were also observed. In a small, preliminary study, patients at risk of stroke (multiple risk factors for stroke, with chronically elevated C-reactive protein, but negative MRI for brain pathology) exhibited increased inflammation in the brain, as indicated by PET imaging. These findings show that brain inflammation occurs in animals, and tentatively in humans, harbouring risk factors for stroke associated with elevated systemic inflammation. Thus a "primed" inflammatory environment in the brain may exist in individuals at risk of stroke and this can be adequately recapitulated in appropriate co-morbid animal models., (Copyright © 2011 Elsevier Inc. All rights reserved.)

It remains uncertain why some plaque ruptures trigger acute coronary syndrome (ACS), whereas others do not. We investigated the anatomic features and tissue factor (TF) expression at the sites of plaque rupture in 42 patients presenting with ACS (n = 23) or stable angina (n = 19). Intravascular ultrasound examination was performed before directional coronary atherectomy. Specimens were stained with antibodies against TF, CD68 positive phagocytic cells, and smooth muscle cells; and intravascular ultrasound and immunohistochemistry results were compared. Baseline demographic and clinical characteristics, as well as vessel and lumen sizes at both reference and lesion sites, were comparable in the two groups. However, the remodeling index and plaque burden at lesion sites were significantly greater in the ACS than in the stable angina group. The TF-immunopositive areas were significantly greater in the ACS than in the stable angina group (0.07%; IQR [0.02-0.16%] vs. 0.02%; IQR [0.01-0.05%], P = 0.022), whereas the proportions of CD68-positive and smooth muscle cell areas were similar. There was a significant correlation between areas positive for TF and those positive for CD68 (r = 0.83, P < 0.001). In conclusion, ruptured plaques in patients with ACS show stronger TF expression, a greater plaque burden, and a higher remodeling index than do plaques in those with stable angina, suggesting that both lesion morphology and local thrombogenicity are related to clinical symptoms after plaque rupture.

An inflammatory response is a pathological hallmark of amyotrophic lateral sclerosis (ALS), a relentless and devastating degenerative disease of motoneurons. This response is not simply a late consequence of motoneuron degeneration, but actively contributes to the balance between neuroprotection and neurotoxicity; initially infiltrating lymphocytes and microglia slow disease progression, while later, they contribute to the acceleration of disease. Since motor weakness begins in the hindlimbs of ALS mice and only later involves the forelimbs, we determined whether differential protective versus injurious inflammatory responses in the cervical and lumbar spinal cords explained the temporally distinct clinical disease courses between the limbs of these mice. Densitometric evaluation of immunohistochemical sections and quantitative RT-PCR (qRT-PCR) demonstrated that CD68 and CD11c were differentially increased in their spinals cords. qRT-PCR revealed that protective and anti-inflammatory factors, including BDNF, GDNF, and IL-4, were increased in the cervical region compared with the lumbar region. In contrast, the toxic markers TNF-α, IL-1β and NOX2 were not different between ALS mice cervical and lumbar regions. T lymphocytes were observed infiltrating lumbar spinal cords of ALS mice prior to the cervical region; mRNA levels of the transcription factor gata-3 (Th2 response) were differentially elevated in the cervical cord of ALS mice whereas t-bet (Th1 response) was increased in the lumbar cord. These results reinforce the important balance between specific protective/injurious inflammatory immune responses in modulating clinical outcomes and suggest that the delayed forelimb motor weakness in ALS mice is partially explained by augmented protective responses in the cervical spinal cords., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Phosphatidylserine (PS), which is normally located on the inner leaflet of the plasma membrane, translocates to the outer leaflet at the early stage of apoptosis. The PS externalization provides a signal for phagocytes to initiate uptake of apoptotic cells. After phagocytosis of apoptotic cells, phagocytes induce the secretion of anti-inflammatory mediators including prostaglandin E(2) (PGE(2)). PS-containing liposomes (PSLs) can mimic the effects of apoptotic cells on phagocytes to induce the secretion of PGE(2). PSLs induce the PGE(2) secretion from microglia without induction of either cyclooxygenase (COX)-2 or microsomal prostaglandin E synthase (mPGES)-1. PSLs are found to rather utilize COX-1/mPGES-2 system to produce PGE(2) secretion and then shift microglia and macrophages from pro- to anti-inflammatory phenotype by an autocrine action of PGE(2). Moreover, PSLs inhibit the maturation of dendritic cells and osteoclast precursors. Therefore, PSLs will be potential pharmacological interventions for inflammatory and immune diseases through feedback mechanism utilizing PGE(2).

In vitro and limited in vivo evidence suggests that reactive oxygen species derived from NADPH oxidases (NOX-ROS) play an important role in inflammatory responses by enhancing the activity of redox-sensitive cell signaling pathways and transcription factors. Here, we investigated the role of NOX-ROS in TNFα-induced acute inflammatory responses in vivo, using mice deficient in the gp91(phox) (NOX2) or p47(phox) subunits of NADPH oxidase. Age- and body weight-matched C57BL/6J wild-type (WT) and gp91(phox) or p47(phox) knockout mice were injected intraperitoneally with 50 μg TNFα/kg bw or saline vehicle control and sacrificed at various time points up to 24 h. Compared to WT mice, gp91(phox -/-) mice exhibited significantly diminished (P<0.05) TNFα-induced acute inflammatory responses in the lungs but not other tissues, including heart, liver, and kidney, as evidenced by decreased activation of the redox-sensitive transcription factor NF-κB, and decreased gene expression of interleukin (IL)-1β, IL-6, TNFα, E-selectin, and other cellular adhesion molecules. Similar results were observed in p47(phox -/-) mice. Interestingly, decreased lung inflammation in knockout mice was accompanied by increased leukocyte infiltration into the lungs compared to other tissues. Our data suggest that phagocytic NOX-ROS signaling plays a critical role in promoting TNFα-induced, NF-κB-dependent acute inflammatory responses and tissue injury specifically in the lungs, which is effected by preferential leukocyte infiltration., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Extravasation of neutrophils and monocytes is a hallmark event in acute and chronic inflammation. Owing to recent improvements in optical imaging techniques, the classical leukocyte extravasation cascade has been refined with intermediate steps being added. Further studies have shown tissue specific leukocyte recruitment patterns, thus allowing for more selective targeting. Here we focus on recent advances in intravital imaging of leukocyte recruitment by means of optical imaging techniques and emphasise the translation thereof into tissue-specific recruitment to the lungs, the liver and large arteries.

To investigate the potential of nanoparticles (NPs) composed of poly(γ-glutamic acid) conjugated with l-phenylalanine (γ-PGA-Phe NPs) for the treatment of retinal diseases, γ-PGA-Phe NPs (200nm) were tested with macrophages and microglia in vitro or by intravitreal administration into normal or pathological rat eyes. The anti-inflammatory effects of the NPs containing dexamethasone (DEX-NPs) were examined using qRT-PCR in vitro by counting activated microglia and Fluorogold-labeled retinal ganglion cells in the retinas under excitotoxicity or by counting TUNEL (+) photoreceptors in the detached retinas. The NPs were taken up efficiently by cultured macrophages or microglia. At day 7, 60-80% of the diffuse signal remained in the cytoplasm of these cells. In normal rat eyes, the NPs did not accumulate in the retinas and no inflammatory cells were recruited. Conversely, under pathological conditions, the NPs were localized in activated CD11b-positive cells in the retina. DEX-NPs suppressed the expression of TNFα and MCP-1 in cultured macrophages or microglia, the activation of microglia, the loss of retinal ganglion cells (RGCs) in excitotoxic retinas, and the number of TUNEL (+) photoreceptors in detached retinas. These data suggest that γ-PGA-Phe NPs can be a powerful tool for suppressing inflammatory cells in pathological conditions in the retina., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Purpose: Multiple, dot-like, yellow precipitates and subretinal yellow material are sometimes deposited within the area of a serous retinal detachment in central serous chorioretinopathy. We report the incidence and clinical features of these depositions in central serous chorioretinopathy., Methods: Eighty eyes of 75 patients (average age, 50.2 years) with central serous chorioretinopathy were studied retrospectively. Fundus autofluorescence and optical coherence tomography findings were evaluated. Precipitates were defined as those ≤ 63 μm in diameter and subretinal yellow material >63 μm., Results: The mean follow-up period was 17.6 months. Forty-five eyes (56.3%) had dot-like precipitates, and 40 eyes (50.0%) had subretinal yellow material. Fifty-two of 80 eyes (65.0%) had both or at least one of them; of these 52 eyes, 50 eyes (96.2%) had hyperautofluorescence and 42 eyes (80.8%) had high reflectivity on optical coherence tomography. The depositions in 23 eyes were not hyperautofluorescent at the initial examination, but the hyperautofluorescence developed during the follow-up period., Conclusion: Dot-like precipitates and subretinal yellow material were seen in 65% of cases with central serous chorioretinopathy that also showed high reflectivity on optical coherence tomography and hyperautofluorescence during follow-up. These findings may indicate that these formations are associated with shedding of the photoreceptor outer segments and metabolism by phagocytes.

The blockade of sPLA-2, as well as the removal of calcium during the infection with Mycobacterium tuberculosis, prevents necrosis in mononuclear phagocytes. In addition, previous evidence indicates that the necrosis is modulated by cytokines and may condition the inflammatory environment. The production of cytokines and chemokines in response to infection with M. tuberculosis, fatty acid profile and the lactate dehydrogenase activity in mononuclear phagocytes from tuberculosis patients and healthy controls were interrelated using a principal component analysis in order to establish whether there was an association between the induction and effector stages of necrosis with the production of cytokines and chemokines. Differentiation increased the ratio of saturated/unsaturated fatty acids. The oleate and palmitate correlated with differentiation, laureate, arachidonate and linolenate with infection and necrosis correlates with the production of IL-10. Monocytes from tuberculosis patients seem to be lees differentiated ex vivo., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aged or abnormal red blood cells with exposed phosphatidylserine (PSRBCs) are cleared from the circulation by splenic macrophages. In asplenic patients, other mononuclear phagocytic cells in tissues and in circulation may function in this capacity. To better understand these changes and the relationship among splenic status, PS-RBCs, blood monocytes, and serum tumor necrosis factor (TNF-α), a product of mononuclear phagocyte activation, patients with hemoglobin E/β-thalassemia (E/β-Thal) were studied. Whole blood of 20 nonsplenectomized, 20 splenectomized E/β-Thal patients, and 20 healthy subjects was assayed for PS-RBCs; for monocytes, activated monocytes, and monocyte response to lipopolysaccharide stimulation; and serum was assayed for TNF-α. Asplenic E/β-Thal patients had significantly increased (P < 0.05) amounts of PS-RBCs, monocytes, activated monocytes, and levels of serum TNF-α. The amount of PS-RBCs correlated with levels of serum TNF-α, but the amount of activated monocytes did not correlate with either the amount of PS-RBCs or levels of serum TNF-α. Monocyte response to lipopolysaccharide stimulation in asplenic patients was not as efficient as in the other patients or in normals (77 vs. 404, and 304 folds increment, respectively). The results suggest that splenectomy in E/β-Thal patients led to an increased amount of PSRBCs and activation in the mononuclear phagocytic system.

Chronic granulomatous disease (CGD) was characterised half a century ago as a primary immunodeficiency disorder of phagocytic cells resulting in failure to kill a specific spectrum of bacteria and fungi and in concomitant hyperinflammation with widespread tissue granuloma formation. CGD now comprises five genetic defects, each impairing one of five essential subunits of the phagocyte NADPH oxidase generating reactive oxygen species. In the past few years CGD has lead to a new understanding of the importance of phagocyte oxygen metabolism for intra- and extracellular host defence and for resolution of the concomitant inflammatory process. In a not too distant future, this may help to tailor novel pharmacological and cellular interventions to the requirements of individual patients. This review covers recent advances in the pathophysiology of CGD and outlines today's clinical presentation as well as the basic principles for treatment of this relatively rare genetic disease. 'Fatal' granulomatous disease 50 years later has become a chronic inflammatory disorder with a median survival of 30 years and is of interest to both paediatricians and internists.

Triggering of phagocyte apoptosis is a major virulence mechanism used by some successful bacterial pathogens. A central issue in the apoptotic death context is that fully developed apoptosis results in necrotic cell autolysis (secondary necrosis) with release of harmful cell components. In multicellular animals, this occurs when apoptosing cells are not removed by scavengers, mainly macrophages. Secondary necrotic lysis of neutrophils and macrophages may occur in infection when extensive phagocyte apoptosis is induced by bacterial cytotoxins and removal of apoptosing phagocytes is defective because the apoptotic process exceeds the available scavenging capacity or targets macrophages directly. Induction of phagocyte secondary necrosis is an important pathogenic mechanism, as it combines the pathogen evasion from phagocyte antimicrobial activities and the release of highly cytotoxic molecules, particularly of neutrophil origin, such as neutrophil elastase. This pathogenicity mechanism therefore promotes the unrestricted multiplication of the pathogen and contributes directly to the pathology of several necrotizing infections, where extensive apoptosis and necrosis of macrophages and neutrophils are present. Here, examples of necrotizing infectious diseases, where phagocyte secondary necrosis is implicated, are reviewed.

The immunotoxicity of tributyltin (TBT) on marine gastropods has been comparatively little studied although risks to wildlife associated with this compound are well known. In this study, a 30-day trial was conducted to evaluate the immunotoxic effects on abalone (Haliotis diversicolor supertexta) by exposing a range of doses of TBT (0, 2, 10, and 50 ng/L). Innate immune parameters, including phagocytic ability (PA), lysozyme activity, phenoloxidase (PO) level and superoxide dismutase (SOD) activity were monitored at intervals of 5, 15 and 30 days. Haemolymph protein expression profile was also examined at the end of the experiment. The results showed that PA value, lysozyme activity and PO level significantly decreased compared with the controls (P < 0.05), which indicated that TBT exposure markedly suppressed non-specific immune competence. Exposure to TBT also caused variation in protein expression patterns of haemolymph. Among the protein spots of differential expressions, seven proteins from the haemolymph of TBT-treated abalone were successfully identified by MALDI-TOF-MS analysis. Three protein spots increased and were identified as carrier-like peptide, peroxidase 21 precursor and creatine phosphokinase. These proteins are believed to up-regulate in expression as a response to detoxification and antioxidative stress mechanisms. The other four protein spots that down-regulated in TBT-treated groups were identified as aromatase-like protein, protein kinase C, ceruloplasmin and microtubule-actin crosslinking factor 1, and these proteins play an important role in endocrine regulation and immune defense. Taken together, the results demonstrate that TBT impair abalone immunological ability and is a potential immune disruptor., (2010 Elsevier Ltd. All rights reserved.)

Granuloma formation is an inflammatory response of the host against invading pathogens or indigestible substances. We generated mesenteric oil granulomas by injecting pristane into the peritoneal cavity (PC) of mice, and compared oil granuloma formation in the C57BL/6J and BALB/cByJ strains of mice. The formation and kinetics of oil granulomas were distinct between the two strains. In C57BL/6J mice, injected pristane induced oil granuloma formation at both the mesenteric centers (MG) and margins (SG). MG was resolving by 11 weeks, and SG persisted. In BALB/cByJ mice, MG developed slower but persisted longer than in C57BL/6J mice, and SG resolved sooner than in C57BL/6J mice. Injection of India ink revealed that phagocytes were localised mainly to the SG in C57BL/6J mice, but were located diffusely in both MG and SG of BALB/cByJ mice. SG cells expressed more monocyte chemotactic protein-1 (MCP-1) mRNA than MG cells in C57BL/6J mice, but there was no difference in MCP-1 expression between the MG and SG in BALB/cByJ mice. These observations suggest that the recruitment of inflammatory leucocytes under the direction of chemokines differentiates the patterns of granuloma responses to pristane in C57BL/6J and BALB/cByJ mice., (© 2010 The Authors. Journal compilation © 2010 Blackwell Publishing Ltd.)

Translocation (10;17)(p13-15;q12-21) in acute leukemia is rarely reported in the literature. Here, we present both a novel t(10;17) case study and a review of relevant literature on t(10;17) in acute leukemia (10 cases). In summary, we came to the following preliminary conclusions: t(10;17) is associated with poorly differentiated acute leukemia subtype [90%; eight cases of acute myeloid leukemia (AML M0, M1) and one case of acute undifferentiated leukemia], phagocytic activity by blasts occurs (30%), and the survival time was short in three of the seven t(10;17) cases for whom follow-up data were available (median, 8 months). More clinical studies concerning the prognosis, treatment response, and survival of patients with t(10;17) are necessary., (2010 Elsevier Inc. All rights reserved.)

Chronic granulomatous disease (CGD) is an inherited disorder characterized by recurrent infections and deregulated inflammatory responses. CGD is caused by mutations in subunits of the NADPH oxidase, an enzyme that generates reactive oxygen species in phagocytes. To elucidate the contribution of the proinflammatory protease caspase-1 to aberrant inflammatory reactions in CGD, we analyzed cells isolated from patients with defects in the phagocyte oxidase subunits p22phox, p47phox or gp91phox. We report that mononuclear phagocytes from CGD patients activated caspase-1 and produced biologically active interleukin-1beta (IL-1beta) in response to danger signals. Notably, caspase-1 activation and IL-1beta secretion from CGD monocytes was elevated in asymptomatic patients and strongly increased in patients with noninfectious inflammatory conditions. Treatment with IL-1 receptor antagonist reduced IL-1 production in monocytes ex vivo and during medical therapy. Our results identify phagocyte oxidase defective monocytes as a source of elevated IL-1 and provide a potential therapeutic option to ameliorate inflammatory conditions associated with CGD.

Macrophages and dendritic cells originate from a common myeloid precursor. Although several studies compared transcriptional profiles of these cells, not a single study compared their lipid profiles. Therefore, we measured and compared fatty acid (FA) and phospholipid (PL) species composition of granulocyte/macrophage colony-stimulating factor (GM-CSF) plus interleukin 4 (IL-4) and macrophage colony-stimulating factor (M-CSF) differentiated monocytes isolated from healthy volunteers. We found that these two cell types prominently differ in their FA composition. Dendritic cells (DCs) contain lower proportions of C16 and C18 mono-unsaturated FAs, but higher proportions of C20 and C22 poly-unsaturated fatty acids (PUFAs) than phagocytic macrophages. Analysis of PL species profiles revealed that GM-CSF/IL-4 differentiated cells have increased amounts of longer and more desaturated phospatidylethanolamine (PE) and phosphatidylserine (PS) species, but lower amounts of shorter and less desaturated PE and PS species than M-CSF differentiated cells. These cell type specific lipid profiles can be attributed to a differential expression and activity of stearoyl-CoA desaturase (SCD). Taken together, our results show that GM-CSF/IL-4 compared to M-CSF differentiated monocytes have less mono-unsaturated FA and PL species, which are due to lower SCD activity observed in DCs., (Copyright 2010 Elsevier GmbH. All rights reserved.)

Cardiovascular disease is one of the leading causes of death in the elderly. Much of the morbidity and mortality in the elderly is attributable to acute ischemic events leading to myocardial infarction (MI) and death of cardiac myocytes. Evidence has been provided that aging associated with adverse remodeling post MI as demonstrated by less effective myocardial repair, greater infarct expansion, and septal hypertrophy. Expression of osteopontin (OPN) increases in the heart post MI. Transgenic mice studies suggest that increased expression of OPN plays a protective role in post-MI LV remodeling by modulating collagen deposition and fibrosis. OPN, a multifunctional protein, has the potential to influence the molecular and cellular changes associated with infarct healing. The post-MI infarct healing process involves temporarily overlapping phases that include the following--(1) inflammation with migration and adhesion of neutrophils and macrophages, phagocytosis and inflammatory gene expression; (2) tissue repair with fibroblast adhesion and proliferation, myofibroblast differentiation, extracellular matrix deposition and scar formation; and (3) structural and functional remodeling of infarcted and non-infarcted myocardium through cardiac myocyte apoptosis, hypertrophy and myocardial angiogenesis. This review is focused on the expression of OPN in the heart post MI and its role in various phases of infarct healing.

Amphioxus is considered to be the basal chordate. However, the structural and anatomical features of the amphioxus immune system are still elusive. Here we report a profile of structural studies of the amphioxus gill and gut, the first line of defending against microbes, through optical and electron microscopy. The amphioxus gut and gill are characterized by the following morphological criteria compared with vertebrates: primary and secondary lymphoid-like tissue clustered in the gill, a thicker basement membrane with a large villus channel and lack of muscular layer in the gut, along with blood vessels that fill with phagocytes following microbial challenge. The phenomena of tissue repair after microbial invasion was observed, though no phagocytes were observed in the region of tissue necrosis. The epithelium cells of amphioxus gut showed active phagocytosis after the microbial challenge. A small number of free and fixed macrophage-like cells were also found in the amphioxus gut. The current results described the structure of the immune system and cellular defense against infection in a protochordate, which may help us in understanding the structural origin of the vertebrate immune system., (Copyright 2010 Elsevier Ltd. All rights reserved.)

In this study, we introduce an application of flow cytometry for the concurrent detection of phagocytotic cells and surface molecules involved in the phagocytic process. E. coli expressing green fluorescent protein (GFP) were applied as the phagocytosable particles. Blood samples were incubated with E. coli expressing GFP, followed by indirect immunofluorescence using four candidate monoclonal antibodies (mAbs). Granulocytes that had phagocytosed E. coli exhibited high levels of GFP intensity, in contrast to the nonphagocytosed cells. By comparing the level of expression of molecules expressed on phagocytosed granulocytes with that of nonphagocytosed cells by flow cytometry, it enabled the determination of the expression and alteration of the cell surface molecules upon phogocytosis. Of the four mAbs used in this study, upon phagocytosis, molecules recognized by mAbs WK13, COSA5A and COSA33NL were up-regulated. However, CD15 recognized by mAb VIMD5 was downregulated. The proposed method will benefit the study of phagocytic mechanisms in the future.

Background: Infection with Mycobacterium tuberculosis (Mtb) results in different clinical outcomes ranging from asymptomatic containment to rapidly progressing tuberculosis (TB). The mechanisms controlling TB progression in immunologically-competent hosts remain unclear., Methodology/principal Findings: To address these mechanisms, we analyzed TB progression in a panel of genetically heterogeneous (A/SnxI/St) F2 mice, originating from TB-highly-susceptible I/St and more resistant A/Sn mice. In F2 mice the rates of TB progression differed. In mice that did not reach terminal stage of infection, TB progression did not correlate with lung Mtb loads. Nor was TB progression correlated with lung expression of factors involved in antibacterial immunity, such as iNOS, IFN-gamma, or IL-12p40. The major characteristics of progressing TB was high lung expression of the inflammation-related factors IL-1beta, IL-6, IL-11 (p<0.0003); CCL3, CCL4, CXCL2 (p<0.002); MMP-8 (p<0.0001). The major predictors of TB progression were high expressions of IL-1beta and IL-11. TNF-alpha had both protective and harmful effects. Factors associated with TB progression were expressed mainly by macrophages (F4-80(+) cells) and granulocytes (Gr-1(hi)/Ly-6G(hi) cells). Macrophages and granulocytes from I/St and A/Sn parental strains exhibited intrinsic differences in the expression of inflammatory factors, suggesting that genetically determined peculiarities of phagocytes transcriptional response could account for the peculiarities of gene expression in the infected lungs. Another characteristic feature of progressing TB was the accumulation in the infected lungs of Gr-1(dim) cells that could contribute to TB progression., Conclusions/significance: In a population of immunocompetent hosts, the outcome of TB depends on quantitatively- and genetically-controlled differences in the intensity of inflammatory responses, rather than being a direct consequence of mycobacterial colonization. Local accumulation of Gr-1(dim) cells is a newly identified feature of progressing TB. High expression of IL-1beta and IL-11 are potential risk factors for TB progression and possible targets for TB immunomodulation.

The inflammatory nature of atherosclerosis is well established but the agent(s) that incite inflammation in the artery wall remain largely unknown. Germ-free animals are susceptible to atherosclerosis, suggesting that endogenous substances initiate the inflammation. Mature atherosclerotic lesions contain macroscopic deposits of cholesterol crystals in the necrotic core, but their appearance late in atherogenesis had been thought to disqualify them as primary inflammatory stimuli. However, using a new microscopic technique, we revealed that minute cholesterol crystals are present in early diet-induced atherosclerotic lesions and that their appearance in mice coincides with the first appearance of inflammatory cells. Other crystalline substances can induce inflammation by stimulating the caspase-1-activating NLRP3 (NALP3 or cryopyrin) inflammasome, which results in cleavage and secretion of interleukin (IL)-1 family cytokines. Here we show that cholesterol crystals activate the NLRP3 inflammasome in phagocytes in vitro in a process that involves phagolysosomal damage. Similarly, when injected intraperitoneally, cholesterol crystals induce acute inflammation, which is impaired in mice deficient in components of the NLRP3 inflammasome, cathepsin B, cathepsin L or IL-1 molecules. Moreover, when mice deficient in low-density lipoprotein receptor (LDLR) were bone-marrow transplanted with NLRP3-deficient, ASC (also known as PYCARD)-deficient or IL-1alpha/beta-deficient bone marrow and fed on a high-cholesterol diet, they had markedly decreased early atherosclerosis and inflammasome-dependent IL-18 levels. Minimally modified LDL can lead to cholesterol crystallization concomitant with NLRP3 inflammasome priming and activation in macrophages. Although there is the possibility that oxidized LDL activates the NLRP3 inflammasome in vivo, our results demonstrate that crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation. These findings provide new insights into the pathogenesis of atherosclerosis and indicate new potential molecular targets for the therapy of this disease.

Tumor cells lose their capability of self-destruction at the hazard of their transformation; they are actually immortal. The macrophages phagocyting the oncogenous cell (its nucleus or fragment) may not manage to destroy it. Under such conditions, the transformation of the macrophage itself into the oncogenous cell could not be ruled out. In the present work, a new hypothesis for the participation of the immune system in the metastasization of tumors is proposed. The extensive investigation of this mechanism would help to find new ways of cancer forecast and treatment.

Tissue infiltration of phagocytes exacerbates several human pathologies including chronic inflammations or cancers. However, the mechanisms involved in macrophage migration through interstitial tissues are poorly understood. We investigated the role of Hck, a Src-family kinase involved in the organization of matrix adhesion and degradation structures called podosomes. In Hck(-/-) mice submitted to peritonitis, we found that macrophages accumulated in interstitial tissues and barely reached the peritoneal cavity. In vitro, 3-dimensional (3D) migration and matrix degradation abilities, 2 protease-dependent properties of bone marrow-derived macrophages (BMDMs), were affected in Hck(-/-) BMDMs. These macrophages formed few and undersized podosome rosettes and, consequently, had reduced matrix proteolysis operating underneath despite normal expression and activity of matrix metalloproteases. Finally, in fibroblasts unable to infiltrate matrix, ectopic expression of Hck provided the gain-of-3D migration function, which correlated positively with formation of podosome rosettes. In conclusion, spatial organization of podosomes as large rosettes, proteolytic degradation of extracellular matrix, and 3D migration appeared to be functionally linked and regulated by Hck in macrophages. Hck, as the first protein combining a phagocyte-limited expression with a role in 3D migration, could be a target for new anti-inflammatory and antitumor molecules.

Photoreceptor cells maintain a roughly constant length by continuously generating new outer segments from their base while simultaneously releasing mature outer segments engulfed by the retinal pigment epithelium (RPE). Thus postmitotic RPE cells phagocytose an immense amount of material over a lifetime, disposing of photoreceptor cell waste while retaining useful content. This review focuses on current knowledge of outer segment phagocytosis, discussing the steps involved along with their critical participants as well as how various perturbations in outer segment (OS) disposal can lead to retinopathies.

A micropipette aspiration technique was adopted in this study on the viscoelastic properties of phagocytes of atherosclerotic origin. A standard linear solid model (Kelvin model) was employed to fit the experimental data, and the 3 viscoelastic coefficients of the model were used to compare the mechanical properties of the phagocytes in different phases during atherosclerosis development. The experimental results indicated that prior to the formation of atherosclerosis, the deformability of the macrophages matured from monocytes decreased, and their rigidity increased. At the initial stage of atherosclerosis formation, the deformability of the foam-cells decreased further. We believe that the deterioration in the deformability of the cells might reduce their mobility within the arterial wall, thus leading to the genesis of atherosclerosis caused by the stagnation and accumulation of the cells laden with atherogenic lipids within the arterial wall. This finding may have important implication in the researches on arteriosclerosis.

Oxidative stress plays a critical role in the pathogenesis of hypertension. The NADPH oxidase constitutes a major source of superoxide anion in phagocytic cells, and its activation is associated with matrix metalloproteinase (MMP)-9 secretion by these cells. We investigated the effects of the angiotensin II type 1 receptor antagonist losartan and its metabolites (EXP3174 and EXP3179) on NADPH oxidase activity and MMP-9 secretion in human phagocytic cells. EXP3179, but not losartan and EXP3174, dose-dependently inhibited (P<0.05) phorbol myristate acetate and insulin-stimulated NADPH oxidase activity. EXP3179 also inhibited phorbol myristate acetate-induced NADPH oxidase in endothelial cells. In addition, EXP3179 inhibited (P<0.05) both phorbol myristate acetate-stimulated p47phox translocation from cytosol to membranes and protein kinase C activity. Affinity experiments and enzymatic assays confirmed that EXP3179 inhibited several protein kinase C isoforms. EXP3179 also inhibited (P<0.05) phorbol myristate acetate-stimulated MMP-9 secretion. In a study performed in 153 hypertensive patients, phagocytic NADPH oxidase activity was lower (P<0.05) in losartan-treated compared with untreated patients and in patients treated with other angiotensin II type 1 receptor antagonists or with angiotensin-converting enzyme inhibitors. Plasma levels of MMP-9 were lower (P<0.05) in losartan-treated hypertensives compared with the other group of patients. Thus, EXP3179 acts as a blocker of the NADPH oxidase in phagocytic cells by a potential mechanism that targets the protein kinase C signaling pathway. This effect can be involved in reduced MMP-9 secretion by these cells. It is proposed that the EXP3179 metabolite may confer to losartan the specific capacity to reduce oxidative stress mediated by phagocytic cells in hypertensive patients.

Compared with the Toll-like receptor 4 (TLR4) ligand LPS restricted to gram-negative bacteria, few studies have addressed induction of lung inflammation and concomitant leukocyte recruitment in response to TLR2 ligands. This study is the first report showing that selective TLR2 stimulation by its ligand Pam(3)-Cys-Ser-Lys-Lys-Lys-Lys-OH (Pam(3)CSK(4)) within the alveolar compartment promoted lung inflammation in mice and induced the migration of circulatory immune cells including mononuclear phagocytes into the inflamed alveolar space. By using the transgenic CX(3)CR1(+/GFP) mouse strain for high-purity sorting of circulating and alveolar recruited mononuclear phagocytes together with SMART preamplification and whole genome oligonucleotide microarray techniques, we found that alveolar trafficking of mononuclear phagocytes was associated with profound changes of their gene expression profiles (approximately 900 differentially regulated genes postrecruitment). In particular, alveolar recruited mononuclear phagocytes showed upregulated transcripts of genes encoding cytokines/chemokines and pattern recognition receptor (PRR)-associated molecules. Notably, we observed a dynamic change of the genetic program of recruited mononuclear phagocytes obtained from bronchoalveolar lavage fluid at different time points (24 vs. 48 h) post-Pam(3)CSK(4) challenge. In early alveolar recruited mononuclear phagocytes, mRNA levels of both proinflammatory (e.g., TNF-alpha, CCL2, and IL-6) and central anti-inflammatory/ proresolution [e.g., IL-1-receptor antagonist (IL-1RN), CD200 receptor (CD200R), IL-1 receptor-associated kinase (IRAK-M), IL-10, and Bcl-2-associated X protein (Bax)] mediators were found to be highly upregulated simultaneously. In corresponding cells recruited until later time points, transcript levels of anti-inflammatory/proresolution molecules persisted at the same level, whereas mRNA levels of proinflammatory mediators were found to decline. Collectively, our in vivo study identifies genetic programs by which alveolar recruited mononuclear phagocytes may contribute to the development and termination of pneumonia caused by gram-positive bacteria.

There has been an increase in our understanding of the complexity of the T cell response to mycobacterial infection recently. Improved tools have allowed the determination of the location and kinetics of naïve T cell activation in the mouse as well the variety of function of mycobacteria-specific cells in humans. There is also an increased appreciation of the balance required during mycobacterial infection between anti-bacterial activity and control of the immunopathologic response. The integration of the T cell functional data with the consequences of infection should improve rational vaccine design.

CD3-specific Ab therapy results in a transient, self-limiting, cytokine-associated, flu-like syndrome in experimental animals and in patients, but the underlying mechanism for this spontaneous resolution remains elusive. By using an in vivo model of CD3-specific Ab-induced flu-like syndrome, we show in this paper that a single injection of sublethal dose of the Ab killed all TGF-beta1(-/-) mice. The death of TGF-beta1(-/-) mice was associated with occurrence of this uncontrolled flu-like syndrome, as demonstrated by a sustained storm of systemic inflammatory TNF and IFN-gamma cytokines. We present evidence that deficiency of professional phagocytes to produce TGF-beta1 after apoptotic T cell clearance may be responsible, together with hypersensitivity of T cells to both activation and apoptosis, for the uncontrolled inflammation. These findings indicate a key role for TGF-beta1 and phagocytes in protecting the recipients from lethal inflammation and resolving the flu-like syndrome after CD3-specific Ab treatment. The study may also provide a novel molecular mechanism explaining the early death in TGF-beta1(-/-) mice.

Aims: CD36 has been shown to associate with non-receptor Src kinases to activate mitogen-activated protein kinases and trigger cytoskeletal remodelling, important events in foam cell formation and macrophage migration. Yet, its role in regulating circulating mononuclear phagocyte trafficking to atherosclerotic lesions has not been investigated. The aim of the present study was to investigate the role of CD36 in modulating the recruitment of mononuclear phagocytes to the arterial wall and the associated vascular inflammation, using both pharmacological and genetic approaches., Methods and Results: Apolipoprotein E-deficient (apoE(-/-)) mice fed a high-fat, high-cholesterol diet were treated daily with a CD36 ligand, EP 80317 (300 microg/kg), or 0.9% NaCl for 6 or 12 weeks. Forty-eight hours before sacrifice, mice were injected iv with (111)Indium-labelled macrophages. A 65% (P < 0.001) reduction of labelled macrophage accumulation at aortic lesions was observed in EP 80317-treated mice, mainly at the level of the aortic arch and iliac arteries, correlating with a 43% reduction of atherosclerotic lesion areas. This was associated with reduced phosphorylation of the focal adhesion kinase Pyk2 following stimulation with oxidized phospholipid in a Src kinase- and CD36-dependent manner. At the vascular level, EP 80317 treatment reduced the expression of pro-inflammatory proteins, including NADPH oxidase, inducible nitric oxide synthase, vascular endothelial cell adhesion molecule-1, and CCL2 chemokine. Plasma IL-6 levels were also reduced by 40% (P < 0.05). In contrast, none of these proteins was modulated in EP 80317-treated apoE/CD36 double knockout (apoE(-/-)/CD36(-/-)) mice., Conclusion: Our results support a role for CD36 signalling in the regulation of mononuclear phagocyte trafficking to atherosclerotic-prone sites and in the associated vascular wall inflammation.

Aim: The present study was performed to investigate the influence of unloading on the regeneration of atrophied and injured skeletal muscle., Methods: Male mice (C57BL/6J), aged 8 weeks, were used. Cardiotoxin (CTX) was injected into soleus muscles bilaterally. Gravitational unloading on soleus muscle was performed by hind limb suspension for 2 weeks before and additionally 6 weeks after CTX injection in one group. Soleus muscles in the remaining groups were loaded keeping the mice in the cages and were dissected 14, 28 and 42 days after the injection., Results: Recovery of the wet weight and protein content of soleus in the CTX-injected group was inhibited by unloading. Increase in satellite cell number, induced by CTX injection and loading, was also inhibited by unloading. Disappearance of infiltration of mononucleated cells into the necrotic area was also delayed. This phenomenon suggests that regeneration, which is indicated by the appearance of fibres with central nuclei, was inhibited by unloading., Conclusion: Results suggested that loading plays an important role in the activation of the regenerating potential of injured skeletal muscle.

Objective: Patients with systemic lupus erythematosus (SLE) are often characterized by cellular as well as humoral deficiencies in the recognition and phagocytosis of dead and dying cells. The aim of this study was to investigate whether the remnants of apoptotic cells are involved in the induction of inflammatory cytokines in blood-borne phagocytes., Methods: We used ex vivo phagocytosis assays comprising cellular and humoral components and phagocytosis assays with isolated granulocytes and monocytes to study the phagocytosis of secondarily necrotic cell-derived material (SNEC). Cytokines were measured by multiplex bead array technology., Results: We confirmed the impaired uptake of various particulate targets, including immunoglobulin-opsonized beads, by granulocytes and monocytes from patients with SLE compared with healthy control subjects. Surprisingly, blood-borne phagocytes from two-thirds of the patients with SLE took up SNEC, which was rarely phagocytosed by phagocytes from healthy control subjects or patients with rheumatoid arthritis. Supplementation of healthy donor blood with IgG fractions derived from patients with SLE transferred the capability to take up SNEC to the phagocytes of healthy donors. Phagocytosis-promoting immune globulins also induced secretion of huge amounts of cytokines by blood-borne phagocytes following uptake of SNEC., Conclusion: Opsonization of SNEC by autoantibodies from patients with SLE fosters its uptake by blood-borne monocytes and granulocytes. Autoantibody-mediated phagocytosis of SNEC is accompanied by secretion of inflammatory cytokines, fueling the inflammation that contributes to the perpetuation of autoimmunity in SLE.

High mobility group box-1 (HMGB1) is extracellularly released from mononuclear phagocytes by lipopolysaccharide (LPS)-stimulation accompanied with cell death, and plays an important role in septic/endotoxin shock as a late phase mediator. Notably, CAP11 (cationic antibacterial polypeptide of 11-kDa), a member of cathelicidin family of antimicrobial peptides, has a potential to bind with LPS and neutralize the biological activity of LPS. In this context, we previously revealed that CAP11 can suppress the elevation of serum HMGB1 level in mouse endotoxin shock model and protect mice from endotoxin lethality. In the present study, to clarify the inhibitory mechanism of CAP11 on HMGB1 release, we evaluated the effect of CAP11 on the LPS-induced HMGB1 release and apoptotic/necrotic cell death using a murine macrophage cell line RAW264.7. The results indicated that LPS-stimulation induced the release of HMGB1 from RAW264.7 cells, accompanied with both apoptotic and necrotic cell death. Of interest, CAP11 markedly inhibited the binding of LPS to target RAW264.7 cells, and suppressed HMGB1 release as well as necrotic cell death; however, CAP11 could not affect the LPS-induced apoptotic cell death. These observations clearly indicate that CAP11 can efficiently abolish necrotic cell death via the inhibition of LPS-binding to target cells, thereby suppressing the release of HMGB1. Thus, CAP11 could be a therapeutic agent for septic/endotoxin shock, with a potential to regulate the release of HMGB1 from LPS-stimulated mononuclear phagocytes via the suppression of LPS-binding to target cells and prevention of necrotic cell death due to its potent LPS-binding activity.

TNF-alpha is conserved in all vertebrate classes and has been identified in all taxonomic groups of teleost fish. However, its biological activities and its role in infection are largely unknown. Using two complementary fish models, gilthead seabream and zebrafish, we report here that the main proinflammatory effects of fish TNF-alpha are mediated through the activation of endothelial cells. Thus, TNF-alpha promotes the expression of E-selectin and different CC and CXC chemokines in endothelial cells, thus explaining the recruitment and activation of phagocytes observed in vivo in both species. We also found that TLR ligands, and to some extent TNF-alpha, were able to increase the expression of MHC class II and CD83 in endothelial cells, which might suggest a role for fish endothelial cells and TNF-alpha in Ag presentation. Lastly, we found that TNF-alpha increases the susceptibility of the zebrafish to viral (spring viremia of carp virus) and bacterial (Streptococcus iniae) infections. Although the powerful actions of fish TNF-alpha on endothelial cells suggest that it might facilitate pathogen dissemination, it was found that TNF-alpha increased antiviral genes and, more importantly, had little effect on the viral load in early infection. In addition, the stimulation of ZF4 cells with TNF-alpha resulted in increased viral replication. Together, these results indicate that fish TNF-alpha displays different sorts of bioactivity to their mammalian counterparts and point to the complexity of the evolution that has taken place in the regulation of innate immunity by cytokines.

Deficiencies in the recognition and phagocytosis of dead and dying cells have been shown to be one of the main alterations in patients with systemic lupus erythematosus (SLE). Cellular as well as humoral elements play an important role in the clearance of apoptotic and necrotic cells. Non-ingested nuclear material may provide survival signals for autoreactive B-cells and consequently antibodies directed against nuclear structures will be produced. In healthy individuals, nuclear fragments are not phagocytosed in whole blood. Instead, they are mainly degraded by the action of plasma DNases and complement factors. In contrast, the uptake of nuclear fragments by blood-borne phagocytes is increased in most patients with SLE. The phagocytosis of this kind of prey, which might be opsonised by autoantibodies, may contribute to the maintenance of inflammatory responses in SLE.

Phagocyte-derived S100 proteins are endogenous activators of innate immune responses. S100A12 binds to the receptor for advanced glycation end-products, while complexes of S100A8/S100A9 (myeloid-related proteins, MRP8/14; calprotectin) are ligands of toll-like receptor 4. These S100 proteins can be detected in stool. In the present study we analyse the release of S100A12 and MRP8/14 from intestinal tissue. Specimens from patients with Crohn's disease (CD; n = 30), ulcerative colitis (UC; n = 30), irritable bowel syndrome (IBS; n = 30) or without inflammation (n = 30) were obtained during endoscopy. After 24 h culture, S100A12 and MRP8/14 were analysed in supernatants. Endoscopic, histological, laboratory and clinical disease activity measures were documented. We found an increased spontaneous release of S100A12 from tissue in inflammatory bowel disease (IBD). The release of S100A12 into the supernatants was 28-fold enhanced in inflamed tissue when compared to non-inflamed tissue (mean 46.9 vs. 1.7 ng/ml, p < 0.0001). In active CD, release of S100A12 and MRP8/14 was strongly dependent on localization, with little release from sites of active ileal inflammation compared to colonic inflammation. This difference was more pronounced for S100A12 than for MRP8/14. S100A12 and MRP8/14 provoked up-regulation of adhesion molecules and chemokines on human intestinal microvascular endothelial cells (HIMECs) isolated from normal colonic tissue. The direct release of phagocyte-derived S100 proteins from inflamed tissues may reflect secretion from infiltrating neutrophils (S100A12) and also monocytes or epithelial cells (MRP8/14). Via activation of pattern recognition receptors, these proteins promote inflammation in intestinal tissue. The enhanced mucosal release can explain the correlation of fecal markers with disease activity in IBD.

CX3CR1 is expressed on monocytes, dendritic cells, macrophages, subsets of T lymphocytes, and natural killer cells and functions in diverse capacities such as leukocyte adhesion, migration, and cell survival on ligand binding. Expression of the CX3CL1 gene, whose expression product is the sole ligand for CX3CR1, is up-regulated in human lungs with chronic cigarette smoke-induced obstructive lung disease. At present, it is unknown whether CX3CL1 up-regulation is associated with the recruitment and accumulation of immune cells that express CX3CR1. We show that mice chronically exposed to cigarette smoke up-regulate CX3CL1 gene expression, which is associated with an influx of CX3CR1+ cells in the lungs. The increase in CX3CR1+ cells is primarily comprised of macrophages and T lymphocytes and is associated with the development of emphysema. In alveolar macrophages, cigarette smoke exposure increased the expression of both CX3CR1 and CX3CL1 genes. The inducibility of CX3CR1 expression was not solely dependent on a chronic stimulus because lipopolysaccharide up-regulated CX3CR1 in RAW264.7 cells in vitro and in mononuclear phagocytes in vivo. Our findings suggest a mechanism by which macrophages amplify and promote CX3CR1+ cell accumulation within the lungs during both acute and chronic inflammatory stress. We suggest that one function of the CX3CR1-CX3CL1 pathway is to recruit and sustain divergent immune cell populations implicated in the pathogenesis of cigarette smoke-induced emphysema.

Objectives: We have previously reported that pancreatic stellate cells (PSCs) have a phagocytic function. The aim of the present study was to investigate whether engulfment of necrotic acinar cells affects pancreatic fibrogenesis., Methods: Rat pancreatic acinar cells were incubated for 48 hours to induce necrosis, and PSCs were allowed to interact with them for 12 to 48 hours. Annexin V and propidium iodide staining or detection of DNA fragmentation was used to identify cell death., Results: A large number of necrotic acinar cells were engulfed by PSCs. When PSCs were exposed to necrotic acinar cells for 12 hours, the number of living PSCs was significantly lower than among the control PSCs, which were not exposed to necrotic acinar cells. DNA degradation was observed in PSCs that had ingested necrotic acinar cells, and they were Annexin V and propidium iodide positive, suggesting that engulfment of necrotic acinar cells induced PSC death. There was no difference between the concentrations of transforming growth factor-beta in the medium of the PSCs that had engulfed acinar cells and the medium of the control PSCs., Conclusions: Engulfment of necrotic acinar cells by PSCs induces PSC death, suggesting that engulfment of necrotic acinar cells may inhibit the progression of fibrogenesis.

We investigated the roles of the potent, chemotactic antimicrobial proteins S100A8, S100A9, and S100A8/A9 in leukocyte migration in a model of streptococcal pneumonia. We first observed differential secretion of S100A8, S100A9, and S100A8/A9 that preceded neutrophil recruitment. This is partially explained by the expression of S100A8 and S100A9 proteins by pneumocytes in the early phase of Streptococcus pneumoniae infection. Pretreatment of mice with anti-S100A8 and anti-S100A9 Abs, alone or in combination had no effect on bacterial load or mice survival, but caused neutrophil and macrophage recruitment to the alveoli to diminish by 70 and 80%, respectively, without modifying leukocyte blood count, transendothelial migration or neutrophil sequestration in the lung vasculature. These decreases were also associated with a 68% increase of phagocyte accumulation in lung tissue and increased expression of the chemokines CXCL1, CXCL2, and CCL2 in lung tissues and bronchoalveolar lavages. These results show that S100A8 and S100A9 play an important role in leukocyte migration and strongly suggest their involvement in the transepithelial migration of macrophages and neutrophils. They also indicate the importance of antimicrobial proteins, as opposed to classical chemotactic factors such as chemokines, in regulating innate immune responses in the lung.

Quantum dots (QDs) have favorable physical and photochemical properties. In this work, we used QDs fluorescent nanoprobes to follow the migration of inflammatory cells from local tissue to draining lymph node in inflammation resolution. Electric pulse stimulation was used to establish inflammation model in mouse tibialis anterior. QDs injected to inflammatory tissue were found to aggregate and endocytosed by inflammatory cells. While in the draining lymph node, QDs mainly distributed in the T cell area. TEM and confocal observation showed that most of QDs in the draining lymph node were located in the endosomes of monocytes/macrophages. Our work shows that QDs can be used as fluorescent probes to follow migration of cells especially phagocytic cells. Thus QDs may be explored in application in immunology research.

There is rapidly increasing interest in the use of magnetic resonance imaging (MRI) to track cell migration in vivo. Iron oxide MR contrast agents can be detected at micromolar concentrations of iron, and offer sufficient sensitivity for T2*-weighted imaging. Cellular MRI shows potential for assessing aspects of cardiovascular disease. Labeling in vivo and tracking macrophages using iron oxide nanoparticles has been a goal for cellular MRI because macrophages play a pivotal role in the pathophysiology of many human diseases, including atherosclerosis. Cellular MRI has also been using to track transplanted therapeutic cells in myocardial regeneration. This review looked at iron oxide nanoparticles, methods of cell labeling, image acquisition techniques and limitations encountered for visualization. Particular attention was paid to stem cells and macrophages for the cardiovascular system.

Three pediatric and two adult Turkish patients with Crimean Congo Hemorrhagic Fever (CCHF) induced hemophagocytic syndrome (HPS) were admitted to Ondokuz Mayis University Hospital, which is in the Middle Black Sea Region of Turkey. All of them had remarkable hemophagocytosis in the bone marrow with severe bleeding symptoms along with the other known clinical and laboratory findings of CCHF. We would like to present these patients and to discuss the pathophysiology and the effect of acquired HPS on the severity of the disease.

Throughout the process of atherosclerosis, lesional macrophages, smooth muscle cells, and possibly endothelial cells undergo programmed cell death, or apoptosis. Under normal physiologic conditions, apoptotic cells are rapidly cleared by neighboring phagocytes, a process called efferocytosis, which prevents secondary cellular necrosis and inflammation. If efferocytosis is not efficient, necrosis, inflammation, and tissue damage ensue. Mouse models of atherosclerosis offer the best opportunity to understand the mechanisms and consequences of lesional cell apoptosis and efferocytosis in atherogenesis and plaque progression. Studies in mice to date have suggested that properly coupled macrophage apoptosis and efferocytosis in early atherosclerosis limits lesion size. The results of other mouse studies suggest that macrophage and smooth muscle cell apoptosis and defective efferocytosis in advanced lesions promotes plaque necrosis. Future insight into these critically important processes will require additional insight into the molecular and cellular mechanisms that lead to lesional cell apoptosis and efferocytosis as well as new mouse models of plaque disruption and thrombosis. Advances in these areas offer great hope for eventual translation into innovative therapeutic strategies to combat atherothrombotic vascular disease.

Promotion of repair and regeneration following traumatic brain injury remains a challenging clinical problem. While significant efforts have been made to reduce inhibitory extracellular matrix expression following central nervous system injury, much less attention has been given to the role of endogenous reparative matrix proteins, such as fibronectin. Traumatic brain injury leads to increased levels of plasma-derived fibronectin in the brain tissue, though the specific function of this protein following neurotrauma was unknown. In this study, we utilized conditional plasma fibronectin (pFN) knockout mice to examine the role of fibronectin following a traumatic insult. Injured mice deficient in pFN performed significantly worse on both motor and cognitive tasks, had significantly increased lesion volume and apoptotic cell death, and had significantly less phagocytic cells in the injured cortex compared to injured mice with normal pFN levels. Moreover, intravenous injections of fibronectin prior to the injury restored the neural deficits seen in the pFN deficient mice to that of wild type injured mice. These results demonstrate that fibronectin is neuroprotective to the traumatically injured brain and identify a novel target for therapeutic interventions.

Although many biodegradable polymers, such as poly-L-lactic acid and poly-L-glycolic acid, are preferentially composed of biological residues normally present in the human body, implants made of these materials often trigger inflammatory and fibrotic responses. Unfortunately, the mechanisms involved in degradable material-mediated tissue responses remain largely unknown. Using animal implantation and cell culture system models, we found a strong correlation between the rate of material degradation and the degree of inflammatory response to material implants. Furthermore, we have identified that both water-soluble and water-insoluble degradation products are potent triggers of phagocyte activation, including at the least, superoxide production. These results support a new concept that slow degradation may improve the biocompatibility of degradable drug-releasing particles and tissue engineering scaffolds.

The in vitro influence of microcystin-LR (MC-LR) on rainbow trout phagocytic cell functions was studied. The cells isolated from the fish blood were exposed on MC-LR at the concentrations of 1, 5, 10, 20 microg/mL. The viability of the cells after 2, 4 and 24 hour incubation with MC-LR was studied as well as phagocytic cell ability measured as zymozan particle phagocytosis and metabolic activity measured as respiratory burst activity. The toxin caused time- and dose-dependent viability decrease, the strongest after cell exposure on 10 and 20 microg/mL and observed only after 24 hours incubation when 1 microg/mL was applied. The phagocytic ability was elevated in the presence of MC-LR at the dose of 5 microg/mL. MC-LR had also modulatory influence on respiratory burst activity. While the two lower doses caused the stimulation of the parameter, the two higher ones diminished superoxide anion production in the triggered cells. The results show the potency of the toxin to influence the fish phagocytic cell functions.