Rapid Host Defense against Aspergillus fumigatus Involves Alveolar Macrophages with a Predominance of Alternatively Activated Phenotype

Bhatia, Shikha; Fei, Mingjian; Yarlagadda, Manohar; Qi, Zengbiao; Akira, Shizuo; Saijo, Shinobu; Iwakura, Yoichiro; Rooijen, Nico van; Gibson, Gregory A.; Croix, Claudette M. St.; Ray, Anuradha; Ray, Prabir

doi:10.1371/journal.pone.0015943

Cited by 108 publications

(96 citation statements)

References 70 publications

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“…In support, we found that Poly I:C-treated sham-operated animals also demonstrate a decrease in CD11b ϩ CD206 ϩ cells. CD206 is a C-type lectin carbohydrate binding protein expressed by alternatively activated macrophages and associated with recovery and restoration of function (Bhatia et al, 2011). Therefore, our data indicate that poly I:C has a general detrimental effect on "protective" microglia and suggest that, rather than affecting the proinflammatory response, deleterious Poly I:C-mediated effects may instead predominantly downregulate the reparative response.…”

Section: Discussionmentioning

confidence: 71%

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Toll-Like Receptor-3 Activation Increases the Vulnerability of the Neonatal Brain to Hypoxia-Ischemia

Stridh

Mottahedin

Johansson

et al. 2013

Journal of Neuroscience

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Susceptibility and progression of brain injury in the newborn is closely associated with an exacerbated innate immune response, but the underlying mechanisms are often unclear. Toll-like receptors (TLRs) are important innate immune sensors that may influence the vulnerability of the developing brain. In the current study, we provide novel data to show that activation of the viral innate immune receptor TLR-3 sensitizes the neonatal brain to subsequent hypoxic-ischemic (HI) damage. Poly inosinic:poly cytidylic acid (Poly I:C), a synthetic ligand for TLR-3, was administered to neonatal mice 14 h before cerebral HI. Activation of TLR-3 before HI increased infarct volume from 3.0 Ϯ 0.5 to 15.4 Ϯ 2.1 mm 3 and augmented loss of myelin basic protein from 13.4 Ϯ 6.0 to 70.6 Ϯ 5.3%. The sensitizing effect of Poly I:C was specific for the TLR-3 pathway because mice deficient in the TLR-3 adaptor protein Toll/IL-1R domain-containing adaptor molecule-1 (TRIF) did not develop larger brain damage. The increased vulnerability was associated with a TRIF-dependent heightened inflammatory response, including proinflammatory cytokines, chemokines, and the apoptosis-associated mediator Fas, whereas there was a decrease in reparative M2-like CD11b ϩ microglia and phosphorylation of Akt. Because TLR-3 is activated via double-stranded RNA during most viral infections, the present study provides evidence that viral infections during pregnancy or in the neonate could have great impact on subsequent HI brain injury.

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Section: Discussionmentioning

confidence: 71%

“…Neonatal HI decreases Akt phosphorylation (Brywe et al, 2005) and in turn increases axonal injury (Xiong et al, 2012). Akt phosphorylation plays an important role in the TRIF signaling pathway and promotes cell survival in response to innate immune stimulation (Park et al, 2006;Joung et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor-3 Activation Increases the Vulnerability of the Neonatal Brain to Hypoxia-Ischemia

Stridh

Mottahedin

Johansson

et al. 2013

Journal of Neuroscience

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“…These findings may help to reconcile conflicting conclusions in the field about the protective roles of macrophages against A. fumigatus. For example, with clodronate liposome-mediated macrophage depletion in mice, Mircescu et al (12) concluded that macrophages are dispensable for inhibiting germination and host survival, while Bhatia et al (37) reported a protective role for macrophages after showing an increased fungal burden in the absence of macrophages. Our findings, from a model completely dependent on innate immune defenses, indicate that macrophages do in fact contribute to host survival.…”

Section: Discussionmentioning

confidence: 99%

Distinct Innate Immune Phagocyte Responses to Aspergillus fumigatus Conidia and Hyphae in Zebrafish Larvae

et al. 2014

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f Aspergillus fumigatus is the most common filamentous fungal pathogen of immunocompromised hosts, resulting in invasive aspergillosis (IA) and high mortality rates. Innate immunity is known to be the predominant host defense against A. fumigatus; however, innate phagocyte responses to A. fumigatus in an intact host and their contributions to host survival remain unclear. Here, we describe a larval zebrafish A. fumigatus infection model amenable to real-time imaging of host-fungal interactions in live animals. Following infection with A. fumigatus, innate phagocyte populations exhibit clear preferences for different fungal morphologies: macrophages rapidly phagocytose conidia and form aggregates around hyphae, while the neutrophil response is dependent upon the presence of hyphae. Depletion of macrophages rendered host larvae susceptible to invasive disease. Moreover, a zebrafish model of human leukocyte adhesion deficiency with impaired neutrophil function also resulted in invasive disease and impaired host survival. In contrast, macrophage-deficient but not neutrophil-deficient larvae exhibited attenuated disease following challenge with a less virulent (⌬laeA) strain of A. fumigatus, which has defects in secondary metabolite production. Taking these results together, we have established a new vertebrate model for studying innate immune responses to A. fumigatus that reveals distinct roles for neutrophils and macrophages in mediating host defense against IA.

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“…Several studies have indicated that macrophages in the airspace of patients with asthma are functionally different from those from healthy individuals (5,6). In Th2 cytokine-enriched allergic inflammation associated with exposure to parasites or allergen, alternatively activated M2 macrophages are seen in various animal models, although their role remains controversial (7,8). A role for macrophages in the cellular and molecular pathogenesis of Th2 inflammation has not been defined in human disease, and it is still unclear how transformation of the macrophage population in the airspace occurs in response to allergen exposure in patients with asthma.…”

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confidence: 99%

Recruited Alveolar Macrophages, in Response to Airway Epithelial–Derived Monocyte Chemoattractant Protein 1/CCL2, Regulate Airway Inflammation and Remodeling in Allergic Asthma

Lee

Jeong²,

Nyenhuis

et al. 2015

Am J Respir Cell Mol Biol

153

142

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Although alveolar macrophages (AMs) from patients with asthma are known to be functionally different from those of healthy individuals, the mechanism by which this transformation occurs has not been fully elucidated in asthma. The goal of this study was to define the mechanisms that control AM phenotypic and functional transformation in response to acute allergic airway inflammation. The phenotype and functional characteristics of AMs obtained from human subjects with asthma after subsegmental bronchoprovocation with allergen was studied. Using macrophagedepleted mice, the role and trafficking of AM populations was determined using an acute allergic lung inflammation model. We observed that depletion of AMs in a mouse allergic asthma model attenuates Th2-type allergic lung inflammation and its consequent airway remodeling. In both human and mouse, endobronchial challenge with allergen induced a marked increase in monocyte chemotactic proteins (MCPs) in bronchoalveolar fluid, concomitant with the rapid appearance of a monocyte-derived population of AMs. Furthermore, airway allergen challenge of allergic subjects with mild asthma skewed the pattern of AM gene expression toward high levels of the receptor for MCP1 (CCR2/ MCP1R) and expression of M2 phenotypic proteins, whereas most proinflammatory genes were highly suppressed. CCL2/MCP-1 gene expression was prominent in bronchial epithelial cells in a mouse allergic asthma model, and in vitro studies indicate that bronchial epithelial cells produced abundant MCP-1 in response to house dust mite allergen. Thus, our study indicates that bronchial allergen challenge induces the recruitment of blood monocytes along a chemotactic gradient generated by allergen-exposed bronchial epithelial cells.

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Rapid Host Defense against Aspergillus fumigatus Involves Alveolar Macrophages with a Predominance of Alternatively Activated Phenotype

Cited by 108 publications

References 70 publications

Toll-Like Receptor-3 Activation Increases the Vulnerability of the Neonatal Brain to Hypoxia-Ischemia

Toll-Like Receptor-3 Activation Increases the Vulnerability of the Neonatal Brain to Hypoxia-Ischemia

Distinct Innate Immune Phagocyte Responses to Aspergillus fumigatus Conidia and Hyphae in Zebrafish Larvae

Recruited Alveolar Macrophages, in Response to Airway Epithelial–Derived Monocyte Chemoattractant Protein 1/CCL2, Regulate Airway Inflammation and Remodeling in Allergic Asthma

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