The Role of CC Chemokine Receptor 6 in Host Defense in a Model of Invasive Pulmonary Aspergillosis

Phadke, Anagha P.; Akangire, Gangaram; Park, Stacy J.; Lira, Sérgio A.; Mehrad, Borna

doi:10.1164/rccm.200602-256oc

Cited by 49 publications

(79 citation statements)

References 70 publications

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“…DCs are an important effector cell during invasive aspergillosis. The Mehrad group showed that CCR6-deficient mice were significantly more susceptible to invasive aspergillosis than were CCR6-sufficient mice (15). CCR6 and its ligand, CCL20, are responsible for the migration of immature DCs to sights of inflammation, including the lung (16,17,41,42).…”

Section: Discussionmentioning

confidence: 99%

“…4). It has been previously reported that DCs provide protection against invasive aspergillosis and that mice lacking adequate numbers of DCs are susceptible to disease (15). Therefore, antifungal responses in CCR7 Ϫ/Ϫ chimeras appear to be the result of an enhanced accumulation of DCs.…”

Section: Wild-type or Ccr7mentioning

confidence: 98%

“…In addition to effector cell production of cytokines in response to A. fumigatus, several chemokines and their receptors have been reported to play a significant role during invasive aspergillosis (10,(13)(14)(15). A key element of DC function is the ability to migrate to sites of inflammation and infection, which is mediated by CCR6 expressed on immature DCs (16,17).…”

mentioning

confidence: 99%

“…Ϫ/Ϫ mice fail to recruit adequate DC numbers to the lung following conidia challenge, and they consequently had significantly enhanced morbidity and mortality compared with wildtype mice (15). Another study, using human DCs, showed that upon internalization of Aspergillus conidia, DCs significantly upregulated their expression of CCR7, in addition to antifungal cytokines (18,19).…”

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confidence: 99%

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CCR7 Deficiency on Dendritic Cells Enhances Fungal Clearance in a Murine Model of Pulmonary Invasive Aspergillosis

Hartigan

Westwick²,

Járai³

et al. 2009

The Journal of Immunology

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Aspergillus fumigatus is a sporulating fungus found ubiquitously in the environment and is easily cleared from immunocompetent hosts. Invasive aspergillosis develops in immunocompromised patients, and is a leading cause of mortality in hematopoietic stem cell transplant recipients. CCR7 and its ligands, CCL19 and CCL21, are responsible for the migration of dendritic cells from sites of infection and inflammation to secondary lymphoid organs. To investigate the role of CCR7 during invasive aspergillosis, we used a well-characterized neutropenic murine model. During invasive aspergillosis, mice with a CCR7 deficiency in the hematopoietic compartment exhibited increased survival and less pulmonary injury compared with the appropriate wild-type control. Flow cytometric analysis of the chimeric mice revealed an increase in the number of dendritic cells present in the lungs of CCR7-deficient chimeras following infection with Aspergillus conidia. An adoptive transfer of dendritic cells into neutropenic mice provided a protective effect during invasive aspergillosis, which was further enhanced with the adoptive transfer of CCR7-deficient dendritic cells. Additionally, CCR7-deficient dendritic cells activated in vitro with Aspergillus conidia expressed higher TNF-α, CXCL10, and CXCL2 levels, indicating a more activated cellular response to the fungus. Our results suggest that the absence of CCR7 is protective during invasive aspergillosis in neutropenic mice. Collectively, these data demonstrate a potential deleterious role for CCR7 during primary immune responses directed against A. fumigatus.

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Section: Discussionmentioning

confidence: 99%

Section: Wild-type or Ccr7mentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

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CCR7 Deficiency on Dendritic Cells Enhances Fungal Clearance in a Murine Model of Pulmonary Invasive Aspergillosis

Hartigan

Westwick²,

Járai³

et al. 2009

The Journal of Immunology

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“…In vivo neutrophil depletion was induced by intraperitoneal administration of 400 mg of monoclonal antibody (mAb) against Ly6G (clone 1A8; Bio X Cell, West Lebanon, NH) or isotype control mAb (clone 2A3; Bio X Cell) as described (20). Methods for tissue harvest (21), bronchoalveolar lavage, and isolation of bone marrow neutrophils (22) and histology (19,21) have been described previously.…”

Section: Methodsmentioning

confidence: 99%

Adenosine A_2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia

Barletta¹,

Cagnina

Burdick

et al. 2012

Am J Respir Crit Care Med

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Rationale: Activation of the adenosine A 2B receptor (A 2B R) promotes antiinflammatory effects in diverse biological settings, but the role of this receptor in antimicrobial host defense in the lung has not been established. Gram-negative bacillary pneumonia is a common and serious illness associated with high morbidity and mortality, the treatment of which is complicated by increasing rates of antibiotic resistance. Objectives: To test the hypothesis that absence of adenosine A 2B receptor signaling promotes host defense against bacterial pneumonia. Methods: We used a model of Klebsiella pneumoniae pneumonia in wild-type mice and mice with targeted deletion of the A 2B R. Host responses were compared in vivo and leukocyte responses to the bacteria were examined in vitro. Measurements and Main Results: A 2B R -/-mice demonstrated enhanced bacterial clearance from the lung and improved survival after infection with K. pneumoniae compared with wild-type controls, an effect that was mediated by bone marrow-derived cells. Leukocyte recruitment to the lungs and expression of inflammatory cytokines did not differ between A 2B R -/-and wild-type mice, but A 2B R -/-neutrophils exhibited sixfold greater bactericidal activity and enhanced production of neutrophil extracellular traps compared with wild-type neutrophils when incubated with K. pneumoniae. Consistent with this finding, bronchoalveolar lavage fluid from A 2B R -/-mice with Klebsiella pneumonia contained more extracellular DNA compared with wild-type mice with pneumonia. Conclusions: These data suggest that the absence of A 2B R signaling enhances antimicrobial activity in gram-negative bacterial pneumonia.Keywords: neutrophil; extracellular traps; pneumonia; adenosine Pneumonia is a leading cause of hospitalization in the United States and is the most common infectious cause of death (1, 2). Aerobic gram-negative bacilli are the most common cause of health care-associated pneumonia; mortality rates from gram-negative pneumonia range from 30 to 60% with antimicrobial therapy (3, 4). The emergence of multiresistant strains of gram-negative bacteria, combined with limited development of new antimicrobial therapies, has exacerbated the need for new approaches to combating these pathogens (5-7). Therapy aimed at augmenting the host response has the potential to enhance bacterial clearance and improve outcomes, and could provide a new avenue for therapeutic advances in combating gramnegative pneumonia, including infections that are caused by antibiotic-resistant pathogens.Adenosine, a breakdown product of ATP, is a potent signaling molecule released from a variety of cells to dampen inflammation, limit tissue destruction, and promote repair (8, 9). In response to cellular stress or tissue injury, the extracellular concentration of adenosine can increase 100-fold. Adenosine acts on four widely expressed G protein-coupled receptors: A 1 , A 2A , A 2B , and A 3 , with variable expression among different cells. The adenosine A 2B receptor (A 2B R) has been shown to en...

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CCL20/CCR6 blockade enhances immunity to RSV by impairing recruitment of DC

et al. 2010

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Chemokines are important mediators of the immune response to pathogens, but can also promote chronic inflammatory states. Chemokine receptor 6 (CCR6) is found on immature DC and effector/memory T cells, and binds a single ligand, CCL20, with high affinity. Here, we investigated the role of CCL20 and CCR6 in a pulmonary viral infection caused by RSV, a ubiquitous virus that can cause severe pulmonary complications. Neutralization of CCL20 during RSV infection significantly reduced lung pathology and favored a Th1 effector response. CCR6-deficient animals recapitulated this phenotype, and additionally showed enhanced viral clearance when compared with WT mice. No differences were observed in migration of T cells to the lungs of CCR6 À/À animals; however, a significant reduction was observed in numbers of conventional DC (cDC), but not plasmacytoid DC, in CCR6 À/À mice. A pathogenic phenotype could be reconstituted in CCR6 À/À mice by supplying cDC into the airway, indicating that mere number of cDC dictates the adverse response. Our data suggest that blockade of the CCL20/CCR6 pathway provides an environment whereby the attenuated recruitment of cDC alters the balance of innate immune cells and mediates the efficient antiviral response to RSV.Key words: Chemokines . DC . Mucosal immunity IntroductionRSV is a pervasive virus that is the most common cause of hospitalization in children under the age of 2 [1]. RSV can also adversely affect the elderly and immunocompromised individuals, causing severe lower respiratory tract infection [2]. Although both Th1 and Th2 effector responses may be generated, Th2 immunity is responsible for RSV-associated pathology, including airway damage and mucus hypersecretion [3]. RSV represents a recurrent problem throughout life because immunologic memory never fully develops [4]. Furthermore, studies have demonstrated a correlation between early exposure to RSV and the later development of asthma [5,6]. No vaccine currently exists, and early attempts to develop a vaccine proved detrimental, as individuals inoculated with a formalin-inactivated form of virus demonstrated enhanced pulmonary eosinophilia and Th2 responses [7]. Clearly, further investigation is needed to clarify the fine balance between immune protection and pathology during RSV infection.Chemokines are key mediators of leukocyte recruitment during pathogenic insult, and also play a prominent role in homeostasis [8]. Most chemokines are promiscuous in that they can bind multiple receptors. CC chemokine receptor 6 (CCR6) is unique in the latter regard in that it binds a single chemokine, CCL20 [9]. CCL20 is a homeostatic chemokine, with a prominent role in organizing lymphoid tissue in the gut [10], but is also upregulated upon pro-inflammatory stimulation [11]. This dual function of CCL20 is evident in the cells expressing its corresponding receptor, CCR6, and contributes to a role for these cells in various immune settings.CCR6 is found on immature DC, B cells, effector/memory T cells and T regulatory cells [12][13][14][...

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The Role of CC Chemokine Receptor 6 in Host Defense in a Model of Invasive Pulmonary Aspergillosis

Cited by 49 publications

References 70 publications

CCR7 Deficiency on Dendritic Cells Enhances Fungal Clearance in a Murine Model of Pulmonary Invasive Aspergillosis

CCR7 Deficiency on Dendritic Cells Enhances Fungal Clearance in a Murine Model of Pulmonary Invasive Aspergillosis

Adenosine A_2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia

CCL20/CCR6 blockade enhances immunity to RSV by impairing recruitment of DC

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The Role of CC Chemokine Receptor 6 in Host Defense in a Model of Invasive Pulmonary Aspergillosis

Cited by 49 publications

References 70 publications

CCR7 Deficiency on Dendritic Cells Enhances Fungal Clearance in a Murine Model of Pulmonary Invasive Aspergillosis

CCR7 Deficiency on Dendritic Cells Enhances Fungal Clearance in a Murine Model of Pulmonary Invasive Aspergillosis

Adenosine A2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia

CCL20/CCR6 blockade enhances immunity to RSV by impairing recruitment of DC

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Adenosine A_2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia