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

Rick Kapur; John W. Semple

doi:10.1084/jem.20210754

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

Frontiers in Immunology ◽

10.3389/fimmu.2020.601614 ◽

2020 ◽

Vol 11 ◽

Author(s):

Yoshinori Sato ◽

Shigeru Tansho-Nagakawa ◽

Tsuneyuki Ubagai ◽

Yasuo Ono

Keyword(s):

Mouse Model ◽

Immune Responses ◽

Acinetobacter Baumannii ◽

Alveolar Macrophages ◽

Post Infection ◽

Pulmonary Inflammation ◽

Cell Subset ◽

Dendritic Cell Subset ◽

Immune Functions ◽

Cd11b Expression

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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Wnt/β-catenin signaling regulates lipopolysaccharide-altered polarizations of RAW264.7 cells and alveolar macrophages in mouse lungs

European Journal of Inflammation ◽

10.1177/20587392211059362 ◽

2021 ◽

Vol 19 ◽

pp. 205873922110593

Author(s):

Jiali Yang ◽

Ying Wang ◽

Dandan Yang ◽

Jia Ma ◽

Shuang Wu ◽

...

Keyword(s):

Alveolar Macrophage ◽

Alveolar Macrophages ◽

Macrophage Polarization ◽

Raw264.7 Cells ◽

M1 Polarization ◽

Inflammatory Phenotype ◽

Inflammatory State ◽

Anti Inflammatory

Introduction Macrophages are capable of exerting both proinflammatory and anti-inflammatory functions in response to distinct environmental stimuli, by polarizing into classically inflammatory state (M1) and anti-inflammatory phenotype (M2), respectively. The Wnt/β-catenin signaling plays an important role in the tissue homeostasis and immune regulations, including the macrophage polarizations. However, the molecular mechanism of Wnt/β-catenin signaling in regulating alveolar macrophage polarization in an inflammatory state remains unclear. Methods The Wnt/β-catenin signaling-altered phenotypes of murine macrophage-like RAW264.7 cells in vitro and alveolar macrophage in vivo in both of naïve and lipopolysaccharide-induced inflammation states were accessed by immunoblotting and immunostaining assays. Results The activation of Wnt/β-catenin signaling inhibited macrophage M1 polarization, but promoted alternative M2 polarization in murine RAW264.7 cells under a naïve state. Interestingly, in an LPS-induced inflammation condition, the enhanced Wnt/β-catenin activity suppressed both M1 and M2 polarizations in RAW264.7 cells in vitro, and primary alveolar macrophages of LPS-challenged mice in vivo. Molecular analysis further demonstrated an involvement of Stat signing in regulating Wnt/β-catenin signaling-altered polarizations in mouse alveolar macrophages. Conclusion These results suggest a mechanism by which Wnt/β-catenin signaling modulates macrophage polarization in an inflammation state by regulating the Stat signaling pathway.

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Pleurotus eryngiiAmeliorates Lipopolysaccharide-Induced Lung Inflammation in Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2014/532389 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Junya Kawai ◽

Tsugunobu Andoh ◽

Kenji Ouchi ◽

Satoshi Inatomi

Keyword(s):

Lung Inflammation ◽

Pulmonary Inflammation ◽

Inflammatory Cells ◽

Lavage Fluid ◽

Beneficial Effects ◽

Lps Challenge ◽

Heat Treated ◽

Cultivated Mushroom ◽

Anti Inflammatory ◽

Intranasal Instillation

Pleurotus eryngii(P. eryngii) is consumed as a fresh cultivated mushroom worldwide and demonstrated to have multiple beneficial effects. We investigated the anti-inflammatory effect ofP. eryngiiin mice with acute lung injury (ALI). Intranasal instillation of lipopolysaccharide (LPS) (10 μg/site/mouse) induced marked lung inflammation (increase in the number of inflammatory cells, protein leakage, and production of nitric oxide in bronchoalveolar lavage fluid) as well as histopathological damage in the lung, 6 h after treatment. Mice administered heat-treatedP. eryngii(0.3–1 g/kg, p.o. (HTPE)) 1 h before LPS challenge showed decreased pulmonary inflammation and ameliorated histopathological damage. These results suggest that HTPE has anti-inflammatory effects against ALI. Thus,P. eryngiiitself may also have anti-inflammatory effects and could be a beneficial food for the prevention of ALI induced by bacterial infection.

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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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IL-10 and class 1 histone deacetylases act synergistically and independently on the secretion of proinflammatory mediators in alveolar macrophages

PLoS ONE ◽

10.1371/journal.pone.0245169 ◽

2021 ◽

Vol 16 (1) ◽

pp. e0245169

Author(s):

Brent A. Stanfield ◽

Todd Purves ◽

Scott Palmer ◽

Bruce Sullenger ◽

Karen Welty-Wolf ◽

...

Keyword(s):

Alveolar Macrophages ◽

Histone Deacetylases ◽

Pulmonary Inflammation ◽

Protein Synthesis Inhibitor ◽

Dependent Manner ◽

Synthesis Inhibitor ◽

Proinflammatory Mediators ◽

Chemokine Signaling ◽

Class 1 ◽

Anti Inflammatory

Introduction Anti-inflammatory cytokine IL-10 suppresses pro-inflammatory IL-12b expression after Lipopolysaccharide (LPS) stimulation in colonic macrophages, as part of the innate immunity Toll-Like Receptor (TLR)-NF-κB activation system. This homeostatic mechanism limits excess inflammation in the intestinal mucosa, as it constantly interacts with the gut flora. This effect is reversed with Histone Deacetylase 3 (HDAC3), a class I HDAC, siRNA, suggesting it is mediated through HDAC3. Given alveolar macrophages’ prominent role in Acute Lung Injury (ALI), we aim to determine whether a similar regulatory mechanism exists in the typically sterile pulmonary microenvironment. Methods Levels of mRNA and protein for IL-10, and IL-12b were determined by qPCR and ELISA/Western Blot respectively in naïve and LPS-stimulated alveolar macrophages. Expression of the NF-κB intermediaries was also similarly assessed. Experiments were repeated with AS101 (an IL-10 protein synthesis inhibitor), MS-275 (a selective class 1 HDAC inhibitor), or both. Results LPS stimulation upregulated all proinflammatory mediators assayed in this study. In the presence of LPS, inhibition of IL-10 and/or class 1 HDACs resulted in both synergistic and independent effects on these signaling molecules. Quantitative reverse-transcriptase PCR on key components of the TLR4 signaling cascade demonstrated significant diversity in IL-10 and related gene expression in the presence of LPS. Inhibition of IL-10 secretion and/or class 1 HDACs in the presence of LPS independently affected the transcription of MyD88, IRAK1, Rela and the NF-κB p50 subunit. Interestingly, by quantitative ELISA inhibition of IL-10 secretion and/or class 1 HDACs in the presence of LPS independently affected the secretion of not only IL-10, IL-12b, and TNFα, but also proinflammatory mediators CXCL2, IL-6, and MIF. These results suggest that IL-10 and class 1 HDAC activity regulate both independent and synergistic mechanisms of proinflammatory cytokine/chemokine signaling. Conclusions Alveolar macrophages after inflammatory stimulation upregulate both IL-10 and IL-12b production, in a highly class 1 HDAC-dependent manner. Class 1 HDACs appear to help maintain the balance between the pro- and anti-inflammatory IL-12b and IL-10 respectively. Class 1 HDACs may be considered as targets for the macrophage-initiated pulmonary inflammation in ALI in a preclinical setting.

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Ncf1 Governs Immune Niches in the Lung to Mediate Pulmonary Inflammation in Mice

Frontiers in Immunology ◽

10.3389/fimmu.2021.783944 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mengyao Li ◽

Wentao Zhang ◽

Jing Zhang ◽

Xiaowei Li ◽

Fujun Zhang ◽

...

Keyword(s):

Alveolar Macrophages ◽

Lung Inflammation ◽

Pulmonary Inflammation ◽

Eosinophil Infiltration ◽

Antibody Treatment ◽

Independent Manner ◽

Species Response ◽

Ifn Γ ◽

Group 2 ◽

Th1 Cytokines

Neutrophil cytosolic factor 1 (Ncf1) is a major genetic factor associated with autoimmune diseases and has been identified as a key player in autoimmune mediated inflammation. We addressed the role of Ncf1 in an antigen-induced pulmonary inflammation model, and found that the Ncf1m1j mutation, causing a deficient reactive oxygen species response, alleviated disease. The Ncf1m1j mutation was associated with a reduced inflammatory cell infiltration in airways, but had limited effect on mucus secretion, antibody production and lung fibrosis. The disease remission in the Ncf1 mutated mice was reversed when functional Ncf1 was transgenically expressed in alveolar macrophages, suggesting that the cellular inflammation was depended on functional Ncf1 in alveolar macrophages. By determining cytokine and chemokine profiles in lung and serum, we found that Ncf1 deficiency allowed an increased expression of Th1 cytokines, including TNF-α, IFN-γ and IL-12. Since also epithelial cytokines were found to be regulated by Ncf1, we tested the effect of Ncf1 in IL-33 and IL-25 induced lung inflammation models. Mice with the Ncf1m1j mutation showed less sensitivity to IL-33, but not IL-25, induced lung inflammation, in a macrophage independent manner. The mice with deficient Ncf1 showed a reduced eosinophil infiltration and group 2 innate lymphoid cell (ILC2) activation. The production of IFN-γ in CD4+ T cells was increased, whereas IL-5 and IL-13 in ILC2 were decreased. Importantly, anti-IFN-γ antibody treatment of Ncf1 deficient mice increased eosinophil infiltration and rescued ILC2 activation in the lung. We conclude that Ncf1 deficiency enhances Th1 response, deactivates ILC2, and protects against pulmonitis.

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Coumarinic derivatives show anti-inflammatory effects on alveolar macrophages, but their anti-elastase activity is essential to reduce lung inflammation in vivo

International Immunopharmacology ◽

10.1016/j.intimp.2008.09.009 ◽

2009 ◽

Vol 9 (1) ◽

pp. 49-54 ◽

Cited By ~ 17

Author(s):

Elyse Y. Bissonnette ◽

Guy M. Tremblay ◽

Véronique Turmel ◽

Bernard Pirotte ◽

Michèle Reboud-Ravaux

Keyword(s):

Alveolar Macrophages ◽

Lung Inflammation ◽

Elastase Activity ◽

Anti Inflammatory

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Bone Marrow-Derived Mesenchymal Stromal Cells (MSCs) Modulate the Inflammatory Character of Alveolar Macrophages from Sarcoidosis Patients

Journal of Clinical Medicine ◽

10.3390/jcm9010278 ◽

2020 ◽

Vol 9 (1) ◽

pp. 278 ◽

Cited By ~ 4

Author(s):

Ian McClain Caldwell ◽

Christopher Hogden ◽

Krisztian Nemeth ◽

Michael Boyajian ◽

Miklos Krepuska ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Mesenchymal Stromal Cells ◽

Alveolar Macrophages ◽

Stromal Cells ◽

Cultured Cells ◽

Intracellular Cytokines ◽

Tnf Α ◽

Inflammatory Phenotype ◽

Anti Inflammatory

Sarcoidosis is a devastating inflammatory disease affecting many organs, especially the lungs and lymph nodes. Bone marrow-derived mesenchymal stromal cells (MSCs) can “reprogram” various types of macrophages towards an anti-inflammatory phenotype. We wanted to determine whether alveolar macrophages from sarcoidosis subjects behave similarly by mounting an anti-inflammatory response when co-cultured with MSCs. Fifteen sarcoidosis and eight control subjects underwent bronchoscopy and bronchoalveolar lavage (BAL). Unselected BAL cells (70–94% macrophages) were isolated and cultured with and without MSCs from healthy adults. Following stimulation of the cultured cells with lipopolysaccharide, the medium was removed to measure interleukin 10 and tumor necrosis factor alpha (IL-10 and TNF-α). In two additional sarcoidosis subjects, flow cytometry was used to study intracellular cytokines and surface markers associated with alveolar macrophages to confirm the results. Unselected BAL cells from sarcoidosis subjects co-cultured with MSCs showed a reduction in TNF-α (pro-inflammatory M1) and an increase in IL-10 (anti-inflammatory M2) in 9 of 11 samples studied. Control subject samples showed few, if any, differences in cytokine production. Unselected BAL cells from two additional patients analyzed by flow cytometry confirmed a switch towards an anti-inflammatory state (i.e., M1 to M2) after co-culture with MSCs. These results suggest that, similarly to other macrophages, alveolar macrophages also respond to MSC contacts by changing towards an anti-inflammatory phenotype. Based on our results, we hypothesize that mesenchymal stromal cells applied to the airways might alleviate lung inflammation and decrease steroid need in patients with sarcoidosis.

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