Blockade of the T cell immunoglobulin and mucin domain protein 3 pathway exacerbates sepsis-induced immune deviation and immunosuppression

Zhao, Zhong; Jiang, Xingwei; Kang, Chunyan; Yan, Xuemin; Hou, Chunmei; Yu, Jin; Wang, Renxi; Xiao, He; Zhou, Tingting; Wen, Zhiyuan; Feng, Jie; Chen, G.; Ma, Yuanfang; Shen, Beifen; Li, Y.; Han, Gencheng

doi:10.1111/cei.12401

Cited by 30 publications

(24 citation statements)

References 38 publications

(97 reference statements)

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“…can also activate inflammatory macrophage reactions and promote T cells apoptosis. 26 In this study, we found that Gal-9/Tim-3 axis is largely up-regulated in ALI, which suggests that immune suppression occurs in ALI progression. Noteworthily, our results revealed that DEX exerted a more pronounced role in decreasing Gal-9/ Tim-3 transcriptional expression than NAC, indicating that DEX may relieve ALI-induced immune inhibition and play a potent immunomodulatory effect in ALI.…”

Section: Discussionsupporting

confidence: 51%

“…Enhanced Tim‐3 may impair natural killer cells function during endotoxic shock . It has been suggested that Tim‐3 can also activate inflammatory macrophage reactions and promote T cells apoptosis . In this study, we found that Gal‐9/Tim‐3 axis is largely up‐regulated in ALI, which suggests that immune suppression occurs in ALI progression.…”

Section: Discussionsupporting

confidence: 49%

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Co‐administration of N‐acetylcysteine and dexmedetomidine plays a synergistic effect on protection of LPS‐induced acute lung injury via correcting Th1/Th2/Th17 cytokines imbalance

Qitai

Lin

Chen

et al. 2019

Clin Exp Pharma Physio

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Recently both N‐acetylcysteine (NAC) and Dexmedetomidine (DEX) have shown emerging roles in protection of acute lung injury (ALI). However, how their protective roles work and whether they can provide synergistic effects in ALI remain unknown. Here we explored it from the hot research viewpoint of Th1/Th2/Th17 cytokines balance. Lipopolysaccharide (LPS)‐induced ALI was established and treated with NAC and/or DEX. Mice were divided into Sham group, ALI group, NAC group, DEX group and NAC+DEX group. Mice were sampled at 6, 12 and 24 hours after the model construction. Histopathology, wet to dry ratio and myeloperoxidase (MPO) activity were assessed in lung tissues. Protein concentration and cell count were assessed in bronchoalveolar lavage fluid (BALF). Th1/Th2/Th17 cytokines were assessed in plasma, BALF and lung homogenate. ALI‐induced lung morphological damage, edema and aberrant MPO activity can be attenuated by NAC or DEX and mostly by NAC+DEX. NAC with DEX significantly reduced ALI‐induced protein leakage and cell infiltration in BALF. Th1/Th2/Th17 cytokines imbalance aggravated with ALI progression. NAC, DEX and especially NAC+DEX can effectively correct these unbalanced cytokines. Galectin‐9 and Tim‐3 were transcriptionally up‐regulated in ALI. Combination of NAC with DEX obtained a maximum effect on decreasing Galectin‐9/Tim‐3 expression. In summary, Th1/Th2/Th17 cytokines imbalance is newly found to participate in LPS‐induced ALI. NAC or DEX administration can attenuate ALI by rebalancing Th1/Th2/Th17 cytokines. Their protective roles can be enhanced when co‐administration, because DEX may relieve the Galectin‐9/Tim‐3 axis‐mediated immune suppression.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionsupporting

confidence: 49%

Co‐administration of N‐acetylcysteine and dexmedetomidine plays a synergistic effect on protection of LPS‐induced acute lung injury via correcting Th1/Th2/Th17 cytokines imbalance

Qitai

Lin

Chen

et al. 2019

Clin Exp Pharma Physio

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“…The results revealed that IL‐10, IL‐12, and TNF‐α were decreased in the septic shock patients, which indicated that immune function appeared to be ‘exhausted’ following the excessive inflammatory response. Another research has revealed that block the Tim‐3 pathway leads to enhanced pro‐inflammation by macrophage and T‐helper cells polarization and lymphocyte apoptosis . Hence, the increases in Tim‐3 on monocytes in the sepsis and severe sepsis patients were likely intended to maintain immune homeostasis, and this protective mechanism was broken in the septic shock patients as indicated by the decrease in the Tim‐3 levels in this group.…”

Section: Discussionmentioning

confidence: 93%

Plasma soluble Tim‐3 emerges as an inhibitor in sepsis: sepsis contrary to membrane Tim‐3 on monocytes

Ren

Jiang

et al. 2015

Tissue Antigens

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Immune dysfunction is the main characteristic of sepsis. T cell Ig and mucin domain protein 3 (Tim-3) on the monocytes has been reported to promote immune homeostasis during sepsis, but the influences of plasm soluble Tim-3 (sTim-3) on the immune system during sepsis remain unknown. Here, 100 patients with different severities of sepsis (40 sepsis, 42 severe sepsis, and 18 septic shock) were enrolled in this study. The Tim-3 and human leukocyte antigen-DR (HLA-DR) on the circulating monocytes were detected using flow cytometry. Plasma sTim-3 was detected by enzyme-linked immunosorbent assay. Inflammatory factors and two kinds of A disintegrin and metalloprotease (ADAM) - ADAM10 and ADAM17 were assessed. The Tim-3 and HLA-DR on the monocytes decreased with increasing sepsis severity. The sTim-3 was reduced in the sepsis and severe sepsis patients but was elevated in the septic shock patients who exhibited significant immunosuppression as predicted by HLA-DR. sTim-3 levels were negatively correlated with IL-12 and TNF-α. ADAM10 and ADAM17, sheddases of Tim-3, exhibited trends toward elevations in the septic shock group. In conclusion, sTim-3 was involved in the development of sepsis. The homeostasis-promoting role of the Tim-3 on the monocytes was disrupted, while the inhibitory role of sTim-3 emerged during sepsis-induced immunosuppression.

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“…One recent and important feature of lymphocyte anergy in sepsis is the description of various increased co‐inhibitory receptors expressions: PD‐1 (CD279), LAG‐3 (CD223), CTLA‐4 (CD152), TIM‐3, BTLA (CD272) contributing to the definition of T cell exhaustion as that described in chronic viral infections. In septic patients, although only low levels of expressions were observed at the onset of syndrome; over the first week, these expressions were progressively upregulated on lymphocytes .…”

Section: Lymphocytesmentioning

confidence: 99%

Sepsis‐induced immune alterations monitoring by flow cytometry as a promising tool for individualized therapy

Monneret

Venet

2015

Cytometry Part B Clinical

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Septic syndromes remain a major although largely under-recognized health care problem and represent the first cause of mortality in intensive care units. While sepsis has, for long, been solely described as inducing a tremendous systemic inflammatory response, novel findings indicate that sepsis indeed initiates a more complex immunologic response that varies over time, with the concomitant occurrence of both pro-and anti-inflammatory mechanisms. As a resultant, after a short proinflammatory phase, septic patients enter a stage of protracted immunosuppression. This is illustrated in those patients by reactivation of dormant viruses (CMV or HSV) or infections due to pathogens, including fungi, which are normally pathogenic solely in immunocompromised hosts. Although mechanisms are not totally understood, these alterations might be directly responsible for worsening outcome in patients who survived initial resuscitation as nearly all immune functions are deeply compromised. Indeed, the magnitude and persistence over time of these dysfunctions have been associated with increased mortality and health-care associated infection rate. Consequently, new promising therapeutic avenues are currently emerging from those recent findings such as adjunctive immunostimulation (IFN-g, GM-CSF, IL-7, anti-PD1/L1 antibodies) for the most immunosuppressed patients. Nevertheless, as there is no clinical sign of immune dysfunctions, the prerequisite for such therapeutic intervention relies on our capacity in identifying the patients who could benefit from immunostimulation. To date, the most robust biomarkers of sepsis-induced immunosuppression are measured by flow cytometry. Of them, the decreased expression of monocyte HLA-DR appears as a "gold standard." This review reports on the mechanisms sustaining sepsis-induced immunosuppression and its related biomarkers measurable by flow cytometry. The objective is to integrate the most recent facts in an up-to-date account of clinical results, flow cytometry aspects as well as issues in results standardization for multicenter studies. V C 2015 International Clinical Cytometry Society

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Blockade of the T cell immunoglobulin and mucin domain protein 3 pathway exacerbates sepsis-induced immune deviation and immunosuppression

Cited by 30 publications

References 38 publications

Co‐administration of N‐acetylcysteine and dexmedetomidine plays a synergistic effect on protection of LPS‐induced acute lung injury via correcting Th1/Th2/Th17 cytokines imbalance

Co‐administration of N‐acetylcysteine and dexmedetomidine plays a synergistic effect on protection of LPS‐induced acute lung injury via correcting Th1/Th2/Th17 cytokines imbalance

Plasma soluble Tim‐3 emerges as an inhibitor in sepsis: sepsis contrary to membrane Tim‐3 on monocytes

Sepsis‐induced immune alterations monitoring by flow cytometry as a promising tool for individualized therapy

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