scholarly journals β2 Integrins Control the Severity of Murine Lyme Carditis

2005 ◽  
Vol 73 (6) ◽  
pp. 3242-3250 ◽  
Author(s):  
Mireia Guerau-de-Arellano ◽  
Joseph Alroy ◽  
Brigitte T. Huber
Keyword(s):  
Dendritic Cells ◽  
Lyme Disease ◽  
Lyme Arthritis ◽  
Wild Type ◽  
Β2 Integrin ◽  
Lyme Carditis ◽  
Inflammatory Processes ◽  
Low Levels ◽  
Β2 Integrins

ABSTRACT Infection of C57BL/6 (B6) mice with the Lyme disease spirochete Borrelia burgdorferi can result in development of arthritis and carditis. B. burgdorferi induces expression of β2/CD18 integrins, adhesion molecules that mediate the firm adhesion of leukocytes to the endothelium necessary for cellular extravasation during inflammation. The important role of β2/CD18 integrins during extravasation suggests that these molecules play a role in the development of Lyme arthritis and carditis. The dependency of these inflammatory processes on the β2 integrins was investigated in CD18 hypomorph mice, which express low levels of CD18. The results indicate that CD18 deficiency did not abrogate development of Lyme arthritis or carditis. Moreover, it resulted in increased severity of Lyme carditis. B. burgdorferi-infected CD18 hypomorph mice showed an increased macrophage infiltration of the heart, while they produced lower levels of borreliacidal anti-B. burgdorferi antibodies compared to wild-type mice. In accordance with these results, we demonstrate that dendritic cells from CD18 hypomorph mice secrete higher levels of monocyte/macrophage chemoattractant protein 1 (MCP-1/CCL2) in response to B. burgdorferi. Similarly, we show by real-time PCR that B. burgdorferi-infected hearts from CD18 hypomorph mice express increased levels of MCP-1 RNA compared to wild-type mice. Overall, our results indicate that β2 integrin deficiency does not abrogate B. burgdorferi-induced inflammation; rather, it results in increased recruitment of macrophages into the B. burgdorferi-infected heart, likely due to the increased expression of MCP-1 in this tissue. Thus, β2 integrins may play a regulatory role in B. burgdorferi-induced inflammation beyond mediating adhesion of leukocytes to the endothelium.

scholarly journals Platelet and Erythrocyte Extravasation across Inflamed Corneal Venules Depend on CD18, Neutrophils and Mast Cell Degranulation

2021 ◽  
Vol 22 (14) ◽  
pp. 7360
Author(s):  
Angie De La Cruz ◽  
Aubrey Hargrave ◽  
Sri Magadi ◽  
Justin A. Courson ◽  
Paul T. Landry ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cell Types ◽  
Mast Cell Degranulation ◽  
Wild Type ◽  
Delayed Wound Healing ◽  
Corneal Epithelial ◽  
Corneal Abrasion ◽  
Low Levels ◽  
Endothelial Pores

Platelet extravasation during inflammation is under-appreciated. In wild-type (WT) mice, a central corneal epithelial abrasion initiates neutrophil (PMN) and platelet extravasation from peripheral limbal venules. The same injury in mice expressing low levels of the β2-integrin, CD18 (CD18hypo mice) shows reduced platelet extravasation with PMN extravasation apparently unaffected. To better define the role of CD18 on platelet extravasation, we focused on two relevant cell types expressing CD18: PMNs and mast cells. Following corneal abrasion in WT mice, we observed not only extravasated PMNs and platelets but also extravasated erythrocytes (RBCs). Ultrastructural observations of engorged limbal venules showed platelets and RBCs passing through endothelial pores. In contrast, injured CD18hypo mice showed significantly less venule engorgement and markedly reduced platelet and RBC extravasation; mast cell degranulation was also reduced compared to WT mice. Corneal abrasion in mast cell-deficient (KitW-sh/W-sh) mice showed less venule engorgement, delayed PMN extravasation, reduced platelet and RBC extravasation and delayed wound healing compared to WT mice. Finally, antibody-induced depletion of circulating PMNs prior to corneal abrasion reduced mast cell degranulation, venule engorgement, and extravasation of PMNs, platelets, and RBCs. In summary, in the injured cornea, platelet and RBC extravasation depends on CD18, PMNs, and mast cell degranulation.

scholarly journals Differential attenuation of β2 integrin–dependent and –independent neutrophil migration by Ly6G ligation

2019 ◽  
Vol 3 (3) ◽  
pp. 256-267 ◽  
Author(s):  
Pierre Cunin ◽  
Pui Y. Lee ◽  
Edy Kim ◽  
Angela B. Schmider ◽  
Nathalie Cloutier ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Neutrophil Migration ◽  
Surface Protein ◽  
Joint Inflammation ◽  
Selective Inhibition ◽  
Β2 Integrin ◽  
Β2 Integrins ◽  
Neutrophil Surface

Abstract Antibody ligation of the murine neutrophil surface protein Ly6G disrupts neutrophil migration in some contexts but not others. We tested whether this variability reflected divergent dependence of neutrophil migration on β2 integrins, adhesion molecules that interact with Ly6G at the neutrophil surface. In integrin-dependent murine arthritis, Ly6G ligation attenuated joint inflammation, even though mice lacking Ly6G altogether developed arthritis normally. By contrast, Ly6G ligation had no impact on integrin-independent neutrophil migration into inflamed lung. In peritoneum, the role of β2 integrins varied with stimulus, proving dispensable for neutrophil entry in Escherichia coli peritonitis but contributory in interleukin 1 (IL-1)–mediated sterile peritonitis. Correspondingly, Ly6G ligation attenuated only IL-1 peritonitis, disrupting the molecular association between integrins and Ly6G and inducing cell-intrinsic blockade restricted to integrin-dependent migration. Consistent with this observation, Ly6G ligation impaired integrin-mediated postadhesion strengthening for neutrophils arresting on activated cremaster endothelium in vivo. Together, these findings identify selective inhibition of integrin-mediated neutrophil emigration through Ly6G ligation, highlighting the marked site and stimulus specificity of β2 integrin dependence in neutrophil migration.

scholarly journals 17 Lyme Disease in Eastern Ontario - A Paediatric Centre’s Experience from 2009-2018

2020 ◽  
Vol 25 (Supplement_2) ◽  
pp. e6-e7
Author(s):  
Stephanie Zahradnik ◽  
Nick Barrowman ◽  
Anne Tsampalieros ◽  
Mary-Ann Harrison ◽  
Jennifer Bowes ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Laboratory Data ◽  
Geographic Location ◽  
Retrospective Chart Review ◽  
Lyme Arthritis ◽  
Annual Number ◽  
Eastern Region ◽  
Local Public Health ◽  
Inpatient Ward ◽  
Lyme Carditis

Abstract Background Lyme disease (LD) is caused by the tick-borne bacterium Borrelia burgdorferi. Over the past ten years, robust local public health data indicates that the incidence of LD has increased significantly in the eastern region of Ontario due to the spread of its vector, the blacklegged tick. As a result, we have seen an increase in the number of cases of LD in children at our tertiary paediatric centre, at all stages of infection. Familiarity with Lyme disease is important as incidence increases. We sought to characterize the cases at our centre. Objectives To describe the epidemiology of LD in children at our centre from 2009-2018, as well as the variety of clinical presentations of paediatric LD. Design/Methods We completed a retrospective chart review from 2009-2018 of all cases admitted or seen in the Infectious Disease (ID) clinic or the Emergency Department (ED) with a diagnosis of LD. Demographic, clinical and laboratory data were collected, including geographic location where infection occurred and resource utilization. We used descriptive statistics to describe cases and comparative statistics to determine changes in number of cases over time. Results There were 171 LD cases managed at our centre during this period. Mean age was 7.4 (SD 4.5) years, 89 (52.0%) were male. The annual number of cases from 2009 - 2018 increased from 1 to 44 and peaked in 2017 (47 cases). The highest number of cases occurred among children <6, the lowest in children ≥11. Most cases occurred in summer (60%), with the fewest in winter months (4%). Stage of LD was not documented in 1 case. Of the remainder, 98 (57.6%) cases were early localized, 41 (25.7%) early disseminated and 31 (19.7%) late disseminated LD. Early and late disseminated cases occurred more commonly in the summer and accounted for the majority of admissions. These included neurologic Lyme (lymphocytic meningitis [2, 1.2%], polyneuropathy [1, 0.6%], cranial nerve palsy [13, 7.6%]), Lyme carditis (5, 2.9%), and Lyme arthritis (29, 17.0%). There were 133 (77.8%) patients managed in ED, 66 (38.6%) in the ID clinic and 17 (9.9%) in the inpatient ward; median length of stay was 6 (IQR 5, 9) days, with a range of 1 to 30 days. The most common geographic locations of infection acquisition were Ottawa (120 cases, 71.0%) and Kingston (26, 15.4%). Conclusion Cases of LD managed at our paediatric centre have increased in keeping with population trends, with all LD stages experienced. Severe cases of meningitis, carditis, and arthritis resulted in hospitalization, with increasing numbers over the study period.

Role of eNOS-derived NO in the postischemic anti-inflammatory effects of antecedent ethanol ingestion in murine small intestine

2007 ◽  
Vol 292 (3) ◽  
pp. H1435-H1442 ◽  
Author(s):  
Taiji Yamaguchi ◽  
Kazuhiro Kamada ◽  
Catherine Dayton ◽  
F. Spencer Gaskin ◽  
Mozow Yusof ◽  
...  
Keyword(s):  
Ethanol Exposure ◽  
Ethanol Ingestion ◽  
Leukocyte Rolling ◽  
Wild Type ◽  
No Donor ◽  
Nos Inhibitors ◽  
Low Levels ◽  
Ethanol Preconditioning ◽  
Dependent Mechanism

Ingestion of low levels of ethanol 24 h before [ethanol preconditioning (EPC)] ischemia and reperfusion (I/R) prevents postischemic leukocyte rolling (LR) and adhesion (LA), effects that were abolished by adenosine A2 receptor (ADO-A2R) antagonists or nitric oxide (NO) synthase (NOS) inhibitors. The aims of this study were to determine whether NO derived from endothelial NOS (eNOS) during the period of ethanol exposure triggered entrance into this preconditioned state and whether these events were initiated by an ADO-A2R-dependent mechanism. Ethanol or distilled water vehicle was administered to C57BL/6J [wild type (WT)] or eNOS-deficient (eNOS−/−) mice by gavage. Twenty-four hours later, the superior mesenteric artery was occluded for 45 min. LR and LA were quantified by intravital microscopy after 30 and 60 min of reperfusion. I/R increased LR and LA in WT mice, effects that were abolished by EPC or NO donor preconditioning (NO-PC). NO-PC was not attenuated by coincident administration of an ADO-A2R antagonist. I/R increased LR and LA in eNOS−/− mice to levels comparable with those noted in WT animals. However, EPC only slightly attenuated postischemic LR and LA, whereas NO-PC remained effective as a preconditioning stimulus in eNOS−/− mice. Preconditioning with an ADO-A2R agonist (which we previously demonstrated prevents I/R-induced LR and LA in WT animals) failed to attenuate these postischemic adhesive responses in eNOS−/− mice. Our results indicate that EPC is triggered by NO formed secondary to ADO-A2R-dependent eNOS activation during the period of ethanol exposure 24 h before I/R.

scholarly journals Distinct Roles of Lymphotoxin α and the Type I Tumor Necrosis Factor (TNF) Receptor in the Establishment of Follicular Dendritic Cells from Non–Bone Marrow–derived Cells

1997 ◽  
Vol 186 (12) ◽  
pp. 1997-2004 ◽  
Author(s):  
Mitsuru Matsumoto ◽  
Yang-Xin Fu ◽  
Hector Molina ◽  
Guangming Huang ◽  
Jinho Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Tumor Necrosis ◽  
Type I ◽  
Follicular Dendritic Cells ◽  
Wild Type ◽  
Lymphotoxin Α ◽  
Deficient Mice ◽  
Necrosis Factor

In mice deficient in either lymphotoxin α (LT-α) or type I tumor necrosis factor receptor (TNFR-I), organized clusters of follicular dendritic cells (FDC) and germinal centers (GC) are absent from the spleen. We investigated the role of LT-α and TNFR-I in the establishment of spleen FDC and GC structure by using reciprocal bone marrow (BM) transfer. When LT-α–deficient mice were reconstituted with wild-type BM, FDC organization and the ability to form GC were restored, indicating that the LT-α–expressing cells required to establish organized FDC are derived from BM. The role of LT-α in establishing organized FDC structure was further investigated by the transfer of complement receptor 1 and 2 (CR1/2)–deficient BM cells into LT-α–deficient mice. Organized FDC were identified with both the FDC-M1 and anti-CR1 monoclonal antibodies in these BM-chimeric mice, indicating that these cells were derived from the LT-α–deficient recipient. Thus, expression of LT-α in the BM-derived cells, but not in the non–BM-derived cells, is required for the maturation of FDC from non-BM precursor cells. In contrast, when TNFR-I–deficient mice were reconstituted with wild-type BM, they showed no detectable FDC clusters or GC formation. This indicates that TNFR-I expression on non–BM-derived cellular components is necessary for the establishment of these lymphoid structures. TNFR-I–deficient BM was able to restore FDC organization and GC formation in LT-α–deficient mice, indicating that formation of these structures does not require TNFR-I expression on BM-derived cells. The data in this study demonstrate that FDC organization and GC formation are controlled by both LT-α–expressing BM-derived cells and by TNFR-I-expressing non–BM-derived cells.

The Role of Beta 2 Integrins in Macrophage Migration During Resolution of Inflammation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3600-3600 ◽  
Author(s):  
Yevgeniya Kushchayeva ◽  
Darya Mishchuk ◽  
Tatiana Ugarova
Keyword(s):  
Lymph Nodes ◽  
Conflicts Of Interest ◽  
Fold Increase ◽  
Initial Population ◽  
Blood Monocytes ◽  
Resident Cell ◽  
Low Levels ◽  
Inflammatory Macrophages ◽  
Β2 Integrins

Abstract Abstract 3600 Poster Board III-537 The mobilization of blood monocytes and their differentiation into macrophages during the immune-inflammatory response helps to prepare the tissue for resolution. During the resolution phase of inflammation macrophages do not die locally: some cells emigrate by draining lymphatics whereas some remain at the site of inflammation. The major myelo-monocytic integrin αMβ2 (Mac-1, CD11b/CD18), together with two related integrins αDβ2 (CD11d/CD18) and αXβ2 (CD11c/CD18), mediate critical adhesive reactions of monocyte/macrophages. However, the roles of these adhesion receptors in control of macrophage retention at sites of inflammation and their emigration to lymph nodes are unclear. Using a mouse model of sterile peritonitis induced by thioglycollate injection, we examined the dynamics of macrophage β2 integrins during the resolution phase of inflammation. Macrophages were defined by FACS analyses as a population of cells expressing αMβ2high, αDβ2+ and CD115+. The initial population of resident β2, positive for βDβ2 and negative for αXβ2. The thioglycollate-challenged mice showed a ∼4-fold increase in macrophages on day 3 followed by a progressive decrease to normal resident cell numbers by day 13. Expression of αMβ2 on macrophages on day 3 decreased by 2.5-fold as a result of dilution of the initial population of αMβ2high resident macrophages by infiltrating blood monocytes expressing αMβ2low. However, after day 3, the density of αMβ2 on macrophages gradually increased and by day 13 returned to the high levels characteristic of resident macrophages. By contrast, expression of αDβ2 and αXβ2 on inflammatory macrophages increased by 2-fold by day 6-9 compared to that on resident macrophages and then returned to the resident levels by day 3. Thus, although the number of macrophages decreased from day 3 to day 9 by several fold, the population of macrophages which remained in the peritoneum was enriched in cells expressing the high levels of αMβ2 and αDα2. Tracking migration of fluorescently labeled peritoneal cells demonstrated that a population of macrophages which leaves the inflamed peritoneum and enters lymph nodes consists of cells expressing low levels of αMβ2 and αDβ2. These data suggested that upregulation of β2 integrins, especially αMβ2, may be responsible for the retention of macrophages in the peritoneum. Indeed, the rate of macrophage emigration from the peritoneum in the αMβ2-deficient mice was significantly higher than that in wild-type mice. The results indicate that macrophage emigration from the inflamed site is controlled by the level of integrin αMβ2 and αDβ2 with low expressors being migratory and high expressors remaining in the peritoneum. The data also highlight the importance of integrins αDβ2 and αXβ2 as specific markers of inflammatory macrophages. Disclosures: No relevant conflicts of interest to declare.

Maturation of dendritic cells leads to up-regulation of cellular FLICE-inhibitory protein and concomitant down-regulation of death ligand–mediated apoptosis

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2628-2631 ◽  
Author(s):  
Martin Leverkus ◽  
Henning Walczak ◽  
Alex McLellan ◽  
Hans-Werner Fries ◽  
Gabi Terbeck ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Tumor Necrosis ◽  
Caspase 8 ◽  
Inhibitory Protein ◽  
Cd95 Ligand ◽  
Induction Of Apoptosis ◽  
Low Levels ◽  
Necrosis Factor ◽  
Dc Maturation

Dendritic cells (DCs) disappear from lymph nodes 1 to 2 days after antigen presentation, presumably by apoptosis. To evaluate the role of death ligands in elimination of DCs, we analyzed the sensitivity of human DCs to CD95 ligand (CD95L) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We found mature DCs to be resistant to killing via CD95L or TRAIL, whereas only immature DCs were partially sensitive. However, all DC populations expressed CD95, TRAIL-R2, and TRAIL-R3 at comparable levels, suggesting that sensitivity to death ligand-induced DC apoptosis is not regulated at the receptor level. Interestingly, mature DCs highly expressed the caspase 8 inhibitory protein cFLIP, whereas only low levels were detected in immature DCs. Thus, death ligand sensitivity proved to be dependent on DC maturation and inversely correlated with expression levels of cFLIP. Induction of apoptosis by TRAIL or CD95L does not seem to play a role in the elimination of mature DCs, but instead might serve to regulate immature DC populations.

scholarly journals Aggravated Lyme Carditis in CD11a−/− and CD11c−/− Mice

2005 ◽  
Vol 73 (11) ◽  
pp. 7637-7643 ◽  
Author(s):  
Mireia Guerau-de-Arellano ◽  
Joseph Alroy ◽  
Daniel Bullard ◽  
Brigitte T. Huber
Keyword(s):  
Wild Type ◽  
Lyme Carditis ◽  
Disease Induction ◽  
In Vivo Analysis ◽  
The Common ◽  
Vitro Analysis ◽  
Β2 Integrins ◽  
In Vitro Analysis

ABSTRACT CD18 hypomorph mice expressing reduced levels of the common β2 integrin chain develop aggravated Lyme carditis, compared to that developed by wild-type (WT) mice, upon infection with the spirochete Borrelia burgdorferi. The enhancement of Lyme carditis in these mice is characterized by increased macrophage infiltration, correlating with augmented expression of the monocyte/macrophage chemoattractant protein 1 (MCP-1). The lack of CD18 results in the deficiency of all β2 integrins, i.e., CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1/CR3), CD11c/CD18 (p150,95/CR4), and CD11d/CD18. To determine the roles of the various β2 integrins in controlling the development of aggravated Lyme carditis, disease induction was analyzed in CD11a−/−, CD11b−/−, and CD11c−/− mice. CD11a−/− and CD11c−/− mice, but not CD11b−/− mice, developed aggravated Lyme carditis after exposure to B. burgdorferi. Similarly to CD18 hypomorph mice, CD11c−/− mice expressed higher levels of MCP-1, compared to both WT and CD11a−/− mice, as determined by in vitro analysis of MCP-1 secretion by bone marrow-derived dendritic cells and in vivo analysis of MCP-1 mRNA expression in B. burgdorferi-infected hearts. On the other hand, CD11a deficiency was associated with heightened heart B. burgdorferi burden relative to that of WT mice. Overall, our results suggest that the increased severity of Lyme carditis in CD18 hypomorph mice is caused by deficiency in CD11a or CD11c, possibly via different mechanisms.

scholarly journals Yersinia pseudotuberculosis Efficiently Escapes Polymorphonuclear Neutrophils during Early Infection

2013 ◽  
Vol 82 (3) ◽  
pp. 1181-1191 ◽  
Author(s):  
Linda Westermark ◽  
Anna Fahlgren ◽  
Maria Fällman
Keyword(s):  
Dendritic Cells ◽  
Yersinia Pseudotuberculosis ◽  
Immune Defense ◽  
Polymorphonuclear Neutrophils ◽  
Lymphoid Tissues ◽  
Wild Type ◽  
Mesenteric Lymph Nodes ◽  
Content Type ◽  
Effective Dissemination

ABSTRACTThe human-pathogenic species of the Gram-negative genusYersiniapreferentially target and inactivate cells of the innate immune defense, suggesting that this is a critical step by which these bacteria avoid elimination and cause disease. In this study, bacterial interactions with dendritic cells, macrophages, and polymorphonuclear neutrophils (PMNs) in intestinal lymphoid tissues during earlyYersinia pseudotuberculosisinfection were analyzed. Wild-type bacteria were shown to interact mainly with dendritic cells, but not with PMNs, on day 1 postinfection, while avirulentyopHandyopEmutants interacted with PMNs as well as with dendritic cells. To unravel the role of PMNs during the early phase of infection, we depleted mice of PMNs by using an anti-Ly6G antibody, after which we could see more-efficient initial colonization by the wild-type strain as well as byyopH,yopE, andyopKmutants on day 1 postinfection. Dissemination ofyopH,yopE, andyopKmutants from the intestinal compartments to mesenteric lymph nodes was faster in PMN-depleted mice than in undepleted mice, emphasizing the importance of effective targeting of PMNs by theseYersiniaouter proteins (Yops). In conclusion, escape from interaction with PMNs due to the action of YopH, YopE, and YopK is a key feature of pathogenicYersiniaspecies that allows colonization and effective dissemination.

scholarly journals Tumor-derived extracellular vesicles regulate tumor-infiltrating regulatory T cells via the inhibitory immunoreceptor CD300a

2020 ◽  
Author(s):  
Yuta Nakazawa ◽  
Kazumasa Kanemaru ◽  
Chigusa Nakahashi-Oda ◽  
Akira Shibuya
Keyword(s):  
Dendritic Cells ◽  
Treg Cell ◽  
Cell Activation ◽  
Extracellular Vesicle ◽  
Treg Cells ◽  
Wild Type ◽  
Cell Numbers ◽  
Tumor Microenvironments ◽  
Deficient Mice

AbstractAlthough tumor-infiltrating regulatory T (Treg) cells play a pivotal role in tumor immunity, how Treg cell activation are regulated in tumor microenvironments remains unclear. Here, we found that mice deficient in the inhibitory immunoreceptor CD300a on their dendritic cells (DCs) have increased numbers of Treg cells in tumors and greater tumor growth compared with wild-type mice after transplantation of B16 melanoma. Pharmacological impairment of extracellular vesicle (EV) release decreased Treg cell numbers in CD300a-deficient mice. Coculture of DCs with tumor-derived EV (TEV) induced the internalization of CD300a and the incorporation of EVs into endosomes, in which CD300a inhibited TEV-mediated TLR3-TRIF signaling for activation of the IFN-β-Treg cells axis. We also show that higher expression of CD300A was associated with decreased tumor-infiltrating Treg cells and longer survival time in patients with melanoma. Our findings reveal the role of TEV and CD300a on DCs in Treg cell activation in the tumor microenvironment.

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