Inflammatory Monocytes Drive Influenza A Virus–Mediated Lung Injury in Juvenile Mice

Coates, Bria M.; Staricha, Kelly; Koch, Clarissa M.; Cheng, Yuan; Shumaker, Dale K.; Budinger, G. R. Scott; Perlman, Harris; Misharin, Alexander V.; Ridge, Karen M.

doi:10.4049/jimmunol.1701543

Cited by 93 publications

(90 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To study the contribution of inflammatory monocytes (Ly6C + monocytes) in regulating influenza-associated diseases in Bcl6 ΔLyz2 mice, we crossed Bcl6 ΔLyz2 and Bcl6 fl/fl mice to Ccr2 −/− mice to block inflammatory monocytes trafficking to infected lungs (25,29). Consistent with a previous report (30), CCR2 deficiency did not affect host weight loss in WT mice.…”

Section: Immunology and Inflammationsupporting

confidence: 57%

BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection

Zhu

Zhang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Neutrophils are vital for antimicrobial defense; however, their role during viral infection is less clear. Furthermore, the molecular regulation of neutrophil fate and function at the viral infected sites is largely elusive. Here we report that BCL6 deficiency in myeloid cells exhibited drastically enhanced host resistance to severe influenza A virus (IAV) infection. In contrast to the notion that BCL6 functions to suppress innate inflammation, we find that myeloid BCL6 deficiency diminished lung inflammation without affecting viral loads. Using a series of Cre-transgenic, reporter, and knockout mouse lines, we demonstrate that BCL6 deficiency in neutrophils, but not in monocytes or lung macrophages, attenuated host inflammation and morbidity following IAV infection. Mechanistically, BCL6 bound to the neutrophil gene loci involved in cellular apoptosis in cells specifically at the site of infection. As such, BCL6 disruption resulted in increased expression of apoptotic genes in neutrophils in the respiratory tract, but not in the circulation or bone marrow. Consequently, BCL6 deficiency promoted tissue neutrophil apoptosis. Partial neutrophil depletion led to diminished pulmonary inflammation and decreased host morbidity. Our results reveal a previously unappreciated role of BCL6 in modulating neutrophil apoptosis at the site of infection for the regulation of host disease development following viral infection. Furthermore, our studies indicate that tissue-specific regulation of neutrophil survival modulates host inflammation and tissue immunopathology during acute respiratory viral infection.

show abstract

Section: Immunology and Inflammationsupporting

confidence: 57%

BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection

Zhu

Zhang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…In the present study, MCP-1 was suppressed in vitro in macrophages and in rat models of ALI after DFSC-CM treatment, which would contribute to the reduction of the infiltration of inflammatory cells in vivo. Our results are in good agreement with previous studies demonstrating that MCP-1 is essential for inflammatory infiltration in ALI [47,48] and other reports showing that MSC treatment remarkably decreased the injury score and neutrophil infiltration in the lung [30,49]. Our data demonstrated the antiinflammatory effects of DFSCs and DFSC-CM, at least to some extent, based on their ability to inhibit inflammatory infiltration.…”

Section: Discussionsupporting

confidence: 83%

“…Monocyte chemoattractant protein-1 (MCP-1), also known as CCL2, is closely related to the recruitment of macrophages to the lungs [47] and prolonged elevation of inflammatory cytokines in ALI [48]. In the present study, MCP-1 was suppressed in vitro in macrophages and in rat models of ALI after DFSC-CM treatment, which would contribute to the reduction of the infiltration of inflammatory cells in vivo.…”

Section: Discussionmentioning

confidence: 56%

Dental Follicle Stem Cells Ameliorate Lipopolysaccharide-Induced Inflammation by Secreting TGF-β3 and TSP-1 to Elicit Macrophage M2 Polarization

Chen

Yang

Tian

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Increasing evidence has demonstrated the novel roles of mesenchymal stem cells (MSCs) in immunotherapy. However, difficulty in acquiring these cells and possible ethical issues limited their application. Recently, we have isolated a unique MSC population from dental follicles with potent stem cell-like properties. This study focused on the effects of dental follicle stem cells (DFSCs) on macrophage activation and polarization to determine their role in immunomodulation and to test if DFSCs are a promising cell source for MSC-based immunotherapy. Methods: Rat acute lung injury (ALI) models induced by Lipopolysaccharide (LPS) were applied to test the immune-modulatory effects of DFSC/DFSC-CM in vivo. The pulmonary permeability was determined by the dry / wet weight ratios of the left upper lung lobe. The lung histopathological damage was graded on a 0 to 4+ scale. And the inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were tested by ELISA. Then we established LPS-induced inflamed macrophage models in vitro. Inflammatory cytokine production and polarization marker expression were measured by RT-qPCR, ELISA, western blot and flow cytometric analysis in macrophages following DFSC-CM treatment. The paracrine factors in DFSC-CM were revealed by a RayBiotech Protein Array. Thereafter, neutralization studies were performed to confirm the potential immune regulators in DFSC-CM. Results: The DFSC/DFSC-CM not only attenuated histopathological damage and pulmonary permeability, but also downregulated pro-inflammatory cytokines MCP-1, IL-1, IL-6 and TNF-α, and upregulated anti-inflammatory cytokine IL-10 in BALF. Immunofluorescence staining revealed the increased expression of macrophage M2 marker Arg-1. Further in vitro study revealed that macrophages switched to an anti-inflammatory M2 phenotype when co-cultured with DFSC-CM, characterized by suppressed production of pro-inflammatory cytokines MCP-1, IL-1, IL-6, TNF-α and M1-polarizing markers iNOS and CD86; and increased expression of the anti-inflammatory cytokine IL-10 and the M2-polarizing markers Arg-1 and CD163. A RayBiotech Protein Array revealed 42 differentially expressed (> 2-fold) paracrine factors in DFSC-CM compared with the serum-free Ham’s F-12K medium, among which TGF-β3 and Thrombospondin-1 (TSP-1) were upregulated by 18- and 105-fold, respectively. Neutralization studies confirmed the immunoregulatory roles of TGF-β3 and TSP-1 in macrophage activation and polarization. Conclusion: These results indicated that DFSCs can reprogram macrophages into the anti-inflammatory M2 phenotype, the paracrine factors TGF-β3 and TSP-1 may be one of the underlying mechanisms. This study supports the hypothesis that DFSCs are promising for MSC-based immunotherapy.

show abstract

“…While there are many mechanisms through which these changes in myeloid cells may occur, we postulate that IFN‐γ may enhance injury, which may result in more destruction of alveolar macrophages and greater recruitment of inflammatory monocytes/macrophages from the bone marrow. One mechanism may be similar to that underlying the greater recruitment of inflammatory monocytes and the increased lung injury in juvenile compared to adult mice following infection with influenza A (Coates et al, ). These authors provide evidence that a sustained type I IFN response in juvenile mice leads to continued expression of CCL2 (MCP‐1), more inflammatory monocytes entering the lungs, prolonged expression of cytokines, and enhanced and prolonged lung injury in the juvenile mice (Coates et al, ).…”

Section: Discussionmentioning

confidence: 99%

Effects of IFN‐γ on immune cell kinetics during the resolution of acute lung injury

et al. 2020

View full text Add to dashboard Cite

The immunologic responses that occur early in the acute respiratory distress syndrome (ARDS) elicit immune‐mediated damage. The mechanisms underlying the resolution of ARDS, particularly the role of signaling molecules in regulating immune cell kinetics, remain important questions. Th1‐mediated responses can contribute to the pathogenesis of acute lung injury (ALI). Interferon‐gamma (IFN‐γ) orchestrates early inflammatory events, enhancing immune‐mediated damage. The current study investigated IFN‐γ during resolution in several experimental models of ALI. The absence of IFN‐γ resulted in altered kinetics of lymphocyte and macrophage responses, suggesting that IFN‐γ present in this microenvironment is influential in ALI resolution. Genetic deficiency of IFN‐γ or administering neutralizing IFN‐γ antibodies accelerated the pace of resolution. Neutralizing IFN‐γ decreased the numbers of interstitial and inflammatory macrophages and increased alveolar macrophage numbers during resolution. Our results underline the complexity of lung injury resolution and provide insight into the effects through which altered IFN‐γ concentrations affect immune cell kinetics and the rate of resolution. These findings suggest that therapies that spatially or temporally control IFN‐γ signaling may promote ALI resolution. Identifying and elucidating the mechanisms critical to ALI resolution will allow the development of therapeutic approaches to minimize collateral tissue damage without adversely altering the response to injury.

show abstract

Inflammatory Monocytes Drive Influenza A Virus–Mediated Lung Injury in Juvenile Mice

Cited by 93 publications

References 56 publications

BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection

BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection

Dental Follicle Stem Cells Ameliorate Lipopolysaccharide-Induced Inflammation by Secreting TGF-β3 and TSP-1 to Elicit Macrophage M2 Polarization

Effects of IFN‐γ on immune cell kinetics during the resolution of acute lung injury

Contact Info

Product

Resources

About