Analysis of Immune Responses in Acinetobacter baumannii-Infected Klotho Knockout Mice: A Mouse Model of Acinetobacter baumannii Infection in Aged Hosts

Acinetobacter baumannii is an important opportunistic pathogen that primarily afflicts elderly people. To clarify the pathogenicity of A. baumannii in the elderly, we investigated immune responses to A. baumannii ATCC 19606 infection in klotho knockout (KO) mice, the mouse model of aging. Following intravenous inoculation, the mice seldom displayed severe symptoms. However, the survival rate was 56% at 7 days post-infection. Bacteria were detected in the lungs of klotho KO mice but not klotho wildtype (WT) mice at 7 days post-infection. Neutrophils, eosinophils, interstitial macrophages, and monocyte/dendritic cell subset in the lungs of klotho KO mice were transiently induced after infection with A. baumannii. The number of alveolar macrophages in klotho KO mice was lower than that in klotho WT mice, except for 1 day post-infection. CD11b expression on neutrophils and alveolar macrophages in the lungs of klotho KO mice was seldom upregulated by the infection. These results suggested that immune functions eliminating bacteria in the lungs of klotho KO mice were insufficient. CD11blow conventional DC cells hardly increased in klotho KO mice infected with A. baumannii. Additionally, the production of interleukin (IL)-10 in the sera of klotho KO mice was significantly higher than that in klotho WT mice, whereas that production of interferon-gamma was not detected in the sera of klotho KO mice. These results suggested that acquired immune responses were hardly induced in klotho KO mice. IL-1β, CXCL1, CXCL2, and CCL2 expression was significantly higher in the lungs of klotho KO mice infected with A. baumannii than in those of klotho WT mice at 1 day post-infection. These results suggested that pulmonary inflammation was elicited in klotho KO mice during early infection. The expression levels of proinflammatory cytokines significantly correlated with TLR9 expression in the lungs of klotho KO mice. The collective results demonstrate an A. baumannii infection state in aged hosts and suggest that pulmonary inflammation and bacterial burden should be noted in aged hosts even in the absence of severe symptoms of A. baumannii infection.

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Anthrax Lethal Toxin Impairs Innate Immune Functions of Alveolar Macrophages and Facilitates Bacillus anthracis Survival

Infection and Immunity ◽

10.1128/iai.00275-06 ◽

2006 ◽

Vol 74 (9) ◽

pp. 5029-5034 ◽

Cited By ~ 51

Author(s):

Wilson J. Ribot ◽

Rekha G. Panchal ◽

Katherine C. Brittingham ◽

Gordon Ruthel ◽

Tara A. Kenny ◽

...

Keyword(s):

Immune Responses ◽

Bacillus Anthracis ◽

Nonhuman Primate ◽

Alveolar Macrophages ◽

Lethal Toxin ◽

Innate Immune ◽

Binary Complex ◽

Immune Functions ◽

Anthrax Lethal Toxin ◽

Ames Strain

ABSTRACT Alveolar macrophages (AM) are very important for pulmonary innate immune responses against invading inhaled pathogens because they directly kill the organisms and initiate a cascade of innate and adaptive immune responses. Although several factors contribute to inhalational anthrax, we hypothesized that unimpeded infection of Bacillus anthracis is directly linked to disabling the innate immune functions contributed by AM. Here, we investigated the effects of lethal toxin (LT), one of the binary complex virulence factors produced by B. anthracis, on freshly isolated nonhuman primate AM. Exposure of AM to doses of LT that killed susceptible macrophages had no effect on the viability of AM, despite complete MEK1 cleavage. Intoxicated AM remained fully capable of B. anthracis spore phagocytosis. However, pretreatment of AM with LT resulted in a significant decrease in the clearance of both the Sterne strain and the fully virulent Ames strain of B. anthracis, which may have been a result of impaired AM secretion of proinflammatory cytokines. Our data imply that cytolysis does not correlate with MEK1 cleavage, and this is the first report of LT-mediated impairment of nonhuman primate AM bactericidal activity against B. anthracis.

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Platelets instruct T reg cells and macrophages in the resolution of lung inflammation

Journal of Experimental Medicine ◽

10.1084/jem.20210754 ◽

2021 ◽

Vol 218 (7) ◽

Author(s):

Rick Kapur ◽

John W. Semple

Keyword(s):

Alveolar Macrophages ◽

Lung Inflammation ◽

Potential Role ◽

Pulmonary Inflammation ◽

Immune Functions ◽

Inflammatory Phenotype ◽

Anti Inflammatory

Platelets convey important nonhemostatic immune functions; however, their potential role in resolving pulmonary inflammation remains to be determined. In this issue of JEM, Rossaint et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20201353) reveal that platelets contribute to the resolution of pulmonary inflammation by directly recruiting T regulatory (T reg) cells to the lungs and by transcriptionally reprogramming alveolar macrophages toward an anti-inflammatory phenotype.

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Interleukin 17 Receptor E (IL-17RE) and IL-17C Mediate the Recruitment of Neutrophils during Acute Streptococcus pneumoniae Pneumonia

Infection and Immunity ◽

10.1128/iai.00329-19 ◽

2019 ◽

Vol 87 (11) ◽

Cited By ~ 4

Author(s):

Patrick Steck ◽

Felix Ritzmann ◽

Anja Honecker ◽

Giovanna Vella ◽

Christian Herr ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Alveolar Macrophages ◽

Pulmonary Inflammation ◽

Interleukin 17 ◽

Immune Functions ◽

Necrosis Factor Alpha ◽

Content Type ◽

Tnf Α ◽

Factor Alpha ◽

Functional Receptor

ABSTRACT Neutrophils contribute to lung injury in acute pneumococcal pneumonia. The interleukin 17 receptor E (IL-17RE) is the functional receptor for the epithelial-derived cytokine IL-17C, which is known to mediate innate immune functions. The aim of this study was to investigate the contribution of IL-17RE/IL-17C to pulmonary inflammation in a mouse model of acute Streptococcus pneumoniae pneumonia. Numbers of neutrophils and the expression levels of the cytokine granulocyte colony-stimulating factor (G-CSF) and tumor necrosis factor alpha (TNF-α) were decreased in lungs of IL-17RE-deﬁcient (Il-17re−/−) mice infected with S. pneumoniae. Numbers of alveolar macrophages rapidly declined in both wild-type (WT) and Il-17re−/− mice and recovered 72 h after infection. There were no clear differences in the elimination of bacteria and numbers of blood granulocytes between infected WT and Il-17re−/− mice. The fractions of granulocyte-monocyte progenitors (GMPs) were significantly reduced in infected Il-17re−/− mice. Numbers of neutrophils were significantly reduced in lungs of mice deficient for IL-17C 24 h after infection with S. pneumoniae. These data indicate that the IL-17C/IL-17RE axis promotes the recruitment of neutrophils without affecting the recovery of alveolar macrophages in the acute phase of S. pneumoniae lung infection.

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Exposure to cryopreserved platelets mediates suppression of myeloid dendritic cell subset immune responses

Pathology ◽

10.1016/j.pathol.2016.12.315 ◽

2017 ◽

Vol 49 ◽

pp. S109

Author(s):

Katrina K. Ki ◽

Lacey Johnson ◽

Helen M. Faddy ◽

Robert L. Flower ◽

Denese C. Marks ◽

...

Keyword(s):

Dendritic Cell ◽

Immune Responses ◽

Cell Subset ◽

Dendritic Cell Subset ◽

Myeloid Dendritic Cell

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The Effect of Traditional Chinese Formula Danchaiheji on the Differentiation of Regulatory Dendritic Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/9179470 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Yingxi Li ◽

Dan Chen ◽

Xiaodong Wang ◽

Jingzhi Tong ◽

Keqiu Li ◽

...

Keyword(s):

Dendritic Cells ◽

Mouse Model ◽

High Efficiency ◽

Cell Subset ◽

Underlying Mechanism ◽

Immunosuppressive Agent ◽

Dendritic Cell Subset ◽

Skin Transplantation ◽

Hla Dr ◽

Regulatory Dendritic Cells

Recently, regulatory dendritic cells (DCregs), a newly described dendritic cell subset with potent immunomodulatory function, have attracted increased attention for their utility in treating immune response-related diseases, such as graft-versus-host disease, hypersensitivity, and autoimmune diseases. Danchaiheji (DCHJ) is a traditional Chinese formula that has been used for many years in the clinic. However, whether DCHJ can program dendritic cells towards a regulatory phenotype and the underlying mechanism behind this process remain unknown. Herein, we investigate the effects of traditional Chinese DCHJ on DCregs differentiation and a mouse model of skin transplantation. The current study demonstrates that DCHJ can induce dendritic cells to differentiate into DCregs, which are represented by high CD11b and low CD86 and HLA-DR expression as well as the secretion of IL-10 and TGF-β. In addition, DCHJ inhibited DC migration and T cell proliferation, which correlated with increasedIDOexpression. Furthermore, DCHJ significantly prolonged skin graft survival time in a mouse model of skin transplantation without any liver or kidney toxicity. The traditional Chinese formula DCHJ has the potential to be a potent immunosuppressive agent with high efficiency and nontoxicity.

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Human CD141+ dendritic cells (cDC1) are impaired in patients with advanced melanoma but can be targeted to enhance anti-PD-1 in a humanized mouse model

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001963 ◽

2021 ◽

Vol 9 (3) ◽

pp. e001963

Author(s):

Yoke Seng Lee ◽

Liam J O'Brien ◽

Carina M Walpole ◽

Frances E Pearson ◽

Ingrid M Leal-Rojas ◽

...

Keyword(s):

Mouse Model ◽

Tumor Growth ◽

Cell Subset ◽

Human Melanoma ◽

Advanced Melanoma ◽

Dendritic Cell Subset ◽

Humanized Mouse ◽

Humanized Mouse Model ◽

Hematopoietic Stem ◽

Stage 4

BackgroundThe conventional type 1 dendritic cell subset (cDC1) is indispensable for tumor immune responses and the efficacy of immune checkpoint inhibitor (ICI) therapies in animal models but little is known about the role of the human CD141+ DC cDC1 equivalent in patients with melanoma.MethodsWe developed a flow cytometry assay to quantify and characterize human blood DC subsets in healthy donors and patients with stage 3 and stage 4 metastatic melanoma. To examine whether harnessing CD141+ DCs could improve responses to ICIs in human melanoma, we developed a humanized mouse model by engrafting immunodeficient NSG-SGM3 mice with human CD34+ hematopoietic stem cells (HSCs) from umbilical cord blood followed by transplantation of a human melanoma cell line and treatment with anti-programmed cell death protein-1 (anti-PD-1).ResultsBlood CD141+ DC numbers were significantly reduced in patients with stage 4 melanoma compared with healthy controls. Moreover, CD141+ DCs in patients with melanoma were selectively impaired in their ability to upregulate CD83 expression after stimulation with toll-like receptor 3 (TLR3) and TLR7/8 agonists ex vivo. Although DC numbers did not correlate with responses to anti-PD-1 and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) ICIs, their numbers and capacity to upregulate CD83 declined further during treatment in non-responding patients. Treatment with anti-PD-1 was ineffective at controlling tumor growth in humanized mice but efficacy was enhanced by indirectly expanding and activating DCs in vivo with fms-like tyrosine kinase-3 ligand (Flt3L) and a TLR3 agonist. Moreover, intratumoral injections of CD141+ DCs resulted in reduced tumor growth when combined with anti-PD-1 treatment.ConclusionsThese data illustrate quantitative and qualitative impairments in circulating CD141+ DCs in patients with advanced melanoma and that increasing CD141+ DC number and function is an attractive strategy to enhance immunogenicity and response rates to ICIs.

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