Antisense Oligonucleotide Treatment Enhances the Recovery of Acute Lung Injury through IL-10–Secreting M2-like Macrophage-Induced Expansion of CD4+ Regulatory T Cells

Guo, Zhongliang; Wen, Zhenke; Qin, Andong; Zhou, Yue; Liao, Zhenyuan; Liu, Zhongmin; Liang, Yongjie; Ren, Tao; Xu, Lin

doi:10.4049/jimmunol.1203233

Cited by 43 publications

(44 citation statements)

References 59 publications

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“…In this study, we observed that IL-10 secretion in unstimulated and CSE-exposed cells was higher in COPD alveolar macrophages compared to controls, consistent with the switching of COPD alveolar macrophages towards the M2-like phenotype [39], which is anti-inflammatory and involved in tissue repair [40][41][42]. However, CSE reduced IL-10 secretion in TLR-stimulated cells from both groups; this suggests that CSE causes a suppression of this anti-inflammatory mechanism under conditions of bacterial exposure.…”

Section: Discussionsupporting

confidence: 75%

Effects of cigarette smoke on Toll-like receptor (TLR) activation of chronic obstructive pulmonary disease (COPD) macrophages

Metcalfe

Lea

Hughes

et al. 2014

Clinical and Experimental Immunology

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SummaryChronic obstructive pulmonary disease (COPD) is characterized by an abnormal innate immune response. We have investigated the changes in the innate immune response of COPD alveolar macrophages exposed to both cigarette smoke and Toll-like receptor (TLR) stimulation. COPD and control alveolar macrophages were exposed to cigarette smoke extract (CSE) followed by TLR-2, -4 and -5 ligands [Pam3CSK4, lipopolysaccharide (LPS) and phase I flagellin (FliC), respectively] or non-typeable Haemophilus influenzae (NTHi). CSE exposure suppressed TLR-induced tumour necrosis factor (TNF)-α, interleukin (IL)-6, IL-10 and regulated on activation, normal T cell expressed and secreted (RANTES) production in both COPD and control alveolar macrophages, but had no effect on interleukin 8 (CXCL8) production. Similarly, CSE suppressed NTHi-induced TNF-α but not NTHiinduced CXCL8 production in COPD alveolar macrophages. Gene expression analysis showed that CSE suppressed LPS-induced TNF-α transcription but not CXCL8 transcription in COPD alveolar macrophages. The dampening effect of CSE on LPS-induced cytokine production was associated with a reduction in p38, extracellular signal regulated kinase (ERK) and p65 activation. In conclusion, CSE caused a reduced innate immune response in COPD alveolar macrophages, with the exception of persistent CXCL8 production. This could be a mechanism by which alveolar macrophages promote neutrophil chemotaxis under conditions of oxidative stress and bacterial exposure.

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Section: Discussionsupporting

confidence: 75%

Effects of cigarette smoke on Toll-like receptor (TLR) activation of chronic obstructive pulmonary disease (COPD) macrophages

Metcalfe

Lea

Hughes

et al. 2014

Clinical and Experimental Immunology

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“…We showed previously that miR-155, a proinflammatory miRNA, is differentially regulated by Akt kinases and plays a central role in M1 polarization of macrophages in several inflammatory models (22). Also, miR-155 was found to be important in the pathogenesis of LPS-induced lung injury (50). Yet, in the aseptic model of acidinduced lung injury, an increase in miR-155 expression was not necessary for the initial M1 polarization of macrophages, whereas a decrease in miR-155 levels was associated with the development of M2 phenotype.…”

Section: Discussionmentioning

confidence: 94%

Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

Vergadi

Vaporidi

Theodorakis

et al. 2014

The Journal of Immunology

147

106

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Acute respiratory distress syndrome (ARDS) is a major cause of respiratory failure, with limited effective treatments available. Alveolar macrophages participate in the pathogenesis of ARDS. To investigate the role of macrophage activation in aseptic lung injury and identify molecular mediators with therapeutic potential, lung injury was induced in wild-type (WT) and Akt2−/− mice by hydrochloric acid aspiration. Acid-induced lung injury in WT mice was characterized by decreased lung compliance and increased protein and cytokine concentration in bronchoalveolar lavage fluid. Alveolar macrophages acquired a classical activation (M1) phenotype. Acid-induced lung injury was less severe in Akt2−/− mice compared with WT mice. Alveolar macrophages from acid-injured Akt2−/− mice demonstrated the alternative activation phenotype (M2). Although M2 polarization suppressed aseptic lung injury, it resulted in increased lung bacterial load when Akt2−/− mice were infected with Pseudomonas aeruginosa. miR-146a, an anti-inflammatory microRNA targeting TLR4 signaling, was induced during the late phase of lung injury in WT mice, whereas it was increased early in Akt2−/− mice. Indeed, miR-146a overexpression in WT macrophages suppressed LPS-induced inducible NO synthase (iNOS) and promoted M2 polarization, whereas miR-146a inhibition in Akt2−/− macrophages restored iNOS expression. Furthermore, miR-146a delivery or Akt2 silencing in WT mice exposed to acid resulted in suppression of iNOS in alveolar macrophages. In conclusion, Akt2 suppression and miR-146a induction promote the M2 macrophage phenotype, resulting in amelioration of acid-induced lung injury. In vivo modulation of macrophage phenotype through Akt2 or miR-146a could provide a potential therapeutic approach for aseptic ARDS; however, it may be deleterious in septic ARDS because of impaired bacterial clearance.

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“…Th17 cells and CD4 + CD25 + Foxp3 + Tregs not only exert opposite functions in immune responses, they also share reciprocal developmental pathways. Balancing CD4 + CD25 + Foxp3 + Tregs and Th17 cells in ALI may help maintain the immune system in the steady state and exhibit a therapeutic benefit for this disease …”

Section: Discussionmentioning

confidence: 99%

Recovery from acute lung injury can be regulated via modulation of regulatory T cells and Th17 cells

Wang

Lin

et al. 2018

Scand J Immunol

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Acute lung injury (ALI) is a severe inflammatory disease, for which no specific treatment exists. The decreased ratio of regulatory T cells (CD4+CD25+FoxP3 Tregs) and Th17 cells is implicated in ALI and inflammation. We here investigated whether maintaining the balance of CD4+CD25+Foxp3+Tregs and Th17 cells can alleviate lung injury. For CD4+CD25+FoxP3 Treg depletion, 200 μg of an anti‐CD25 antibody was administered intraperitoneally per mouse on days −3 and −1 before lipopolysaccharide (LPS) instillation. And 150 μg of TGF‐β was administered intraperitoneally per mouse on day 0 after LPS instillation. To down‐regulate of Th17 cells, 200 μg per mouse of isotype, IL‐17 or IL‐22 antibodies were injected intraperitoneally into mice at days 0 after LPS instillation. We detected lung morphology; lung wet‐to‐dry weight ratio; protein concentration, the count of total cells, neutrophils and macrophages, and cytokines in bronchoalveolar lavage fluid (BALF). And we also evaluated the percentage of CD4+CD25+Foxp3+Tregs in lung, and Th17 cells in lung. CD4+CD25+Foxp3+Tregs depletion via anti‐CD25 treatment or TGF‐β neutralization delayed recovery of ALI. The prolonged inflammation was mainly dominated by neutrophils, macrophages and Th17 cells. Furthermore, inhibition of Th17 cells via monoclonal antibodies against IL‐17 and IL‐22 alleviated ALI inflammation by inhibiting the recruitment of neutrophils and macrophages, increasing the number of CD4+CD25+Foxp3+Tregs. Our findings support a critical role for CD4+CD25+Foxp3+Tregs in regulating from ALI pathophysiology, and a potential therapeutic role for the inhibition of Th17 cells in ALI treatment. These findings provide a rationale for treating patients with ALI by modulating CD4+CD25+Foxp3+Tregs and Th17 cells.

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Antisense Oligonucleotide Treatment Enhances the Recovery of Acute Lung Injury through IL-10–Secreting M2-like Macrophage-Induced Expansion of CD4+ Regulatory T Cells

Cited by 43 publications

References 59 publications

Effects of cigarette smoke on Toll-like receptor (TLR) activation of chronic obstructive pulmonary disease (COPD) macrophages

Effects of cigarette smoke on Toll-like receptor (TLR) activation of chronic obstructive pulmonary disease (COPD) macrophages

Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

Recovery from acute lung injury can be regulated via modulation of regulatory T cells and Th17 cells

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