Kupffer Cell-mediated Recruitment of Dendritic Cells to the Liver Crucial for a Host Defense

SummaryAspergillus fumigatus, a ubiquitous mold, is a common cause of invasive aspergillosis (IA) in immunocompromised patients. Host defense against IA relies on lung-infiltrating neutrophils and monocyte-derived dendritic cells (Mo-DCs). Here, we demonstrate that plasmacytoid dendritic cells (pDCs), which are prototypically anti-viral cells, participate in innate immune crosstalk underlying mucosal antifungal immunity. Aspergillus-infected murine Mo-DCs and neutrophils recruited pDCs to the lung by releasing the CXCR3 ligands, CXCL9 and CXCL10, in a Dectin-1/Card9- and type I and III interferon-signaling dependent manner, respectively. During aspergillosis, circulating pDCs entered the lung in response to CXCR3-dependent signals. Via targeted pDC ablation, we found that pDCs were essential for host defense in the presence of normal neutrophil and Mo-DC numbers. Although interactions between pDC and fungal cells were not detected, pDCs regulated neutrophil NADPH oxidase activity and conidial killing. Thus, pDCs act as positive feedback amplifiers of neutrophil effector activity against inhaled mold conidia.

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Important Role for Toll-Like Receptor 9 in Host Defense against Meningococcal Sepsis

Infection and Immunity ◽

10.1128/iai.00615-08 ◽

2008 ◽

Vol 76 (11) ◽

pp. 5421-5428 ◽

Cited By ~ 32

Author(s):

Hong Sjölinder ◽

Trine H. Mogensen ◽

Mogens Kilian ◽

Ann-Beth Jonsson ◽

Søren R. Paludan

Keyword(s):

Dendritic Cells ◽

Inflammatory Response ◽

Host Defense ◽

Meningococcal Disease ◽

Cellular Level ◽

Cytokine Gene Expression ◽

Late Time ◽

Meningococcal Sepsis ◽

Wild Type

ABSTRACT Neisseria meningitidis is a leading cause of meningitis and sepsis. The pathogenesis of meningococcal disease is determined by both bacterial virulence factors and the host inflammatory response. Toll-like receptors (TLRs) are prominent activators of the inflammatory response, and TLR2, -4, and -9 have been reported to be involved in the host response to N. meningitidis. While TLR4 has been suggested to play an important role in early containment of infection, the roles of TLR2 and TLR9 in meningococcal disease are not well described. Using a model for meningococcal sepsis, we report that TLR9−/− mice displayed reduced survival and elevated levels of bacteremia compared to wild-type mice. In contrast, TLR2−/− mice controlled the infection in a manner comparable to that of wild-type mice. TLR9 deficiency was also associated with reduced bactericidal activity in vitro, which was accompanied by reduced production of nitric oxide by TLR9-deficient macrophages. Interestingly, TLR9−/− mice recruited more macrophages to the bloodstream than wild-type mice and produced elevated levels of cytokines at late time points during infection. At the cellular level, activation of signal transduction and induction of cytokine gene expression were independent of TLR2 or TLR9 in macrophages and conventional dendritic cells. In contrast, plasmacytoid dendritic cells relied entirely on TLR9 to induce these activities. Thus, our data demonstrate an important role for TLR9 in host defense against N. meningitidis.

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TheCnes2Locus on Mouse Chromosome 17 Regulates Host Defense against Cryptococcal Infection through Pleiotropic Effects on Host Immunity

Infection and Immunity ◽

10.1128/iai.00697-15 ◽

2015 ◽

Vol 83 (12) ◽

pp. 4541-4554 ◽

Cited By ~ 5

Author(s):

Mitra Shourian ◽

Adam Flaczyk ◽

Isabelle Angers ◽

Barbara C. Mindt ◽

Jörg H. Fritz ◽

...

Keyword(s):

Dendritic Cells ◽

Host Defense ◽

Inbred Mice ◽

Chromosome 17 ◽

Interleukin 12 ◽

Multiparameter Flow Cytometry ◽

Airway Epithelial ◽

Phenotypic Analysis ◽

Mucus Production ◽

Content Type

The genetic basis of natural susceptibility to progressiveCryptococcus neoformansinfection is not well understood. Using C57BL/6 and CBA/J inbred mice, we previously identified three chromosomal regions associated withC. neoformanssusceptibility (Cnes1,Cnes2, andCnes3). To validate and characterize the role ofCnes2during the host response, we constructed a congenic strain on the C57BL/6 background (B6.CBA-Cnes2). Phenotypic analysis of B6.CBA-Cnes2mice 35 days afterC. neoformansinfection showed a significant reduction of fungal burden in the lungs and spleen with higher pulmonary expression of gamma interferon (IFN-γ) and interleukin-12 (IL-12), lower expression of IL-4, IL-5, and IL-13, and an absence of airway epithelial mucus production compared to that in C57BL/6 mice. Multiparameter flow cytometry of infected lungs also showed a significantly higher number of neutrophils, exudate macrophages, CD11b+dendritic cells, and CD4+cells in B6.CBA-Cnes2than in C57BL/6 mice. The activation state of recruited macrophages and dendritic cells was also significantly increased in B6.CBA-Cnes2mice. Taken together, these findings demonstrate that theCnes2interval is a potent regulator of host defense, immune responsiveness, and differential Th1/Th2 polarization followingC. neoformansinfection.

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Depletion of Dendritic Cells Enhances Innate Anti-Bacterial Host Defense through Modulation of Phagocyte Homeostasis

PLoS Pathogens ◽

10.1371/journal.ppat.1002552 ◽

2012 ◽

Vol 8 (2) ◽

pp. e1002552 ◽

Cited By ~ 40

Author(s):

Stella E. Autenrieth ◽

Philipp Warnke ◽

Guido H. Wabnitz ◽

Cecilia Lucero Estrada ◽

Karina A. Pasquevich ◽

...

Keyword(s):

Dendritic Cells ◽

Host Defense ◽

Bacterial Host

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Corrigendum: Virus infection of dendritic cells: portal for host invasion and host defense*

Trends in Microbiology ◽

10.1016/j.tim.2004.09.009 ◽

2004 ◽

Vol 12 (11) ◽

pp. 483

Keyword(s):

Dendritic Cells ◽

Virus Infection ◽

Host Defense ◽

Host Invasion

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Intestinal host defense outcome is dictated by PGE2 production during efferocytosis of infected cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1722016115 ◽

2018 ◽

Vol 115 (36) ◽

pp. E8469-E8478 ◽

Cited By ~ 5

Author(s):

Naiara Naiana Dejani ◽

Allan Botinhon Orlando ◽

Victoria Eugenia Niño ◽

Letícia de Aquino Penteado ◽

Felipe Fortino Verdan ◽

...

Keyword(s):

Dendritic Cells ◽

Host Defense ◽

Inflammatory Responses ◽

Infectious Colitis ◽

E Coli ◽

Ep4 Receptor ◽

Intestinal Pathology ◽

Infected Cells ◽

Th17 Differentiation ◽

Pka Pathway

Inflammatory responses are terminated by the clearance of dead cells, a process termed efferocytosis. A consequence of efferocytosis is the synthesis of the antiinflammatory mediators TGF-β, PGE2, and IL-10; however, the efferocytosis of infected cells favors Th17 responses by eliciting the synthesis of TGF-β, IL-6, and IL-23. Recently, we showed that the efferocytosis of apoptotic Escherichia coli-infected macrophages by dendritic cells triggers PGE2 production in addition to pro-Th17 cytokine expression. We therefore examined the role of PGE2 during Th17 differentiation and intestinal pathology. The efferocytosis of apoptotic E. coli-infected cells by dendritic cells promoted high levels of PGE2, which impaired IL-1R expression via the EP4-PKA pathway in T cells and consequently inhibited Th17 differentiation. The outcome of murine intestinal Citrobacter rodentium infection was dependent on the EP4 receptor. Infected mice treated with EP4 antagonist showed enhanced intestinal defense against C. rodentium compared with infected mice treated with vehicle control. Those results suggest that EP4 signaling during infectious colitis could be targeted as a way to enhance Th17 immunity and host defense.

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