Taurodeoxycholate Increases the Number of Myeloid-Derived Suppressor Cells That Ameliorate Sepsis in Mice

Chang, Semoon; Kim, Youn Hee; Kim, Young Joo; Kim, Young Woo; Moon, Seong-Yong; Lee, Yong Yook; Jung, Jin Sun; Kim, Youngsoo; Jung, Hi Eun; Kim, Tae Joo; Cheong, Taek Chin; Moon, Hye Jung; Cho, Jung Ah; Kim, Hang Rae; Han, Dohyun; Na, Yirang; Seok, Seonho; Cho, Nam Hyuk; Lee, Hai Chon; Nam, Eun Hee; Cho, Hyosuk; Choi, Murim; Minato, Nagahiro; Seong, Seung Yong

doi:10.3389/fimmu.2018.01984

Cited by 47 publications

(39 citation statements)

References 79 publications

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“…Even the restoration of the reduced bile acid TDCA and the elevated amino acid DOPA seems to be a positive regulatory mechanism. TDCA ameliorates systemic inflammation, normalizes blood pressure, prevents kidney injury, and prolongs survival in a mouse sepsis model ( 65 ). DOPA has anti-neuro inflammation effects and improved neuroplasticity in septic mice ( 66 ).…”

Section: Discussionmentioning

confidence: 99%

X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure

et al. 2020

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We previously reported the Bruton's tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib improve outcomes in a mouse model of polymicrobial sepsis. Now we show that genetic deficiency of the BTK gene alone in Xid mice confers protection against cardiac, renal, and liver injury in polymicrobial sepsis and reduces hyperimmune stimulation (“cytokine storm”) induced by an overwhelming bacterial infection. Protection is due in part to enhanced bacterial phagocytosis in vivo , changes in lipid metabolism and decreased activation of NF-κB and the NLRP3 inflammasome. The inactivation of BTK leads to reduced innate immune cell recruitment and a phenotypic switch from M1 to M2 macrophages, aiding in the resolution of sepsis. We have also found that BTK expression in humans is increased in the blood of septic non-survivors, while lower expression is associated with survival from sepsis. Importantly no further reduction in organ damage, cytokine production, or changes in plasma metabolites is seen in Xid mice treated with the BTK inhibitor ibrutinib, demonstrating that the protective effects of BTK inhibitors in polymicrobial sepsis are mediated solely by inhibition of BTK and not by off-target effects of this class of drugs.

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Section: Discussionmentioning

confidence: 99%

X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure

et al. 2020

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“…CD244 is a known marker of myeloid suppressor cells involved in suppressing the activation of neighboring myeloid cells (20,21). Upregulation of CD244 on granulocyte-derived suppressor cells has been shown to reduce the severity of sepsis (21). Our current data reveal that neutrophils conditioned with subclinical low dose of LPS not only express inflammatory adhesion molecules such as ICAM-1 and CD29 but also exhibit reduced expression of CD244.…”

Section: Discussionmentioning

confidence: 50%

“…In addition to inflammatory mediators, neutrophils are known to express suppressor molecules such as CD244. CD244 is a known marker of myeloid suppressor cells involved in suppressing the activation of neighboring myeloid cells (20,21). Upregulation of CD244 on granulocyte-derived suppressor cells has been shown to reduce the severity of sepsis (21).…”

Section: Discussionmentioning

confidence: 99%

Innate Priming of Neutrophils Potentiates Systemic Multiorgan Injury

et al. 2020

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Excessive inflammatory reactions mediated by first-responder cells such as neutrophils contribute to the severity of multiorgan failure associated with systemic injury and infection. Systemic subclinical endotoxemia due to mucosal leakage may aggravate neutrophil activation and tissue injury. However, mechanisms responsible for neutrophil inflammatory polarization are not well understood. In this study, we demonstrate that subclinical low-dose endotoxemia can potently polarize neutrophils into an inflammatory state in vivo and in vitro, as reflected in elevated expression of adhesion molecules such as ICAM-1 and CD29, and reduced expression of suppressor molecule CD244. When subjected to a controlled administration of gut-damaging chemical dextran sulfate sodium, mice conditioned with subclinical dose LPS exhibit significantly elevated infiltration of neutrophils into organs such as liver, colon, and spleen, associated with severe multiorgan damage as measured by biochemical as well as histological assays. Subclinical dose LPS is sufficient to induce potent activation of SRC kinase as well as downstream activation of STAT1/STAT5 in neutrophils, contributing to the inflammatory neutrophil polarization. We also demonstrate that the administration of 4phenylbutyric acid, an agent known to relieve cell stress and enhance peroxisome function, can reduce the activation of SRC kinase and enhance the expression of suppressor molecule CD244 in neutrophils. We show that i.v. injection of 4-phenylbutyric acid conditioned neutrophils can effectively reduce the severity of multiorgan damage in mice challenged with dextran sulfate sodium. Collectively, our data, to our knowledge, reveal novel inflammatory polarization of neutrophils by subclinical endotoxemia conducive for aggravated multiorgan damage as well as potential therapeutic intervention. ImmunoHorizons, 2020, 4: 392-401.

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“…By contrast, transfer of late MDSCs from septic mice (day 12) had the opposite effect . Taurodeoxycholate increased the percentage of G‐MDSCs and, therefore, improved the outcome in septic mice . However, much remains to be investigated regarding the effect of MDSCs in regulating the immune homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…3 Taurodeoxycholate increased the percentage of G-MDSCs and, therefore, improved the outcome in septic mice. 31 However, much remains to be investigated regarding the effect of MDSCs in regulating the immune homeostasis. It is possible that a subset of MDSCs exerts different effects on the progress of sepsis.…”

Section: Discussionmentioning

confidence: 99%

LDK378 inhibits the recruitment of myeloid‐derived suppressor cells to spleen via the p38–GRK2–CCR2 pathway in mice with sepsis

Zhang

Liu

et al. 2019

Immunol Cell Biol

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Myeloid‐derived suppressor cells (MDSCs) are functionally immunosuppressive cells that are persistently increased in abundance and associated with adverse clinical outcomes in sepsis. Here, we investigated the therapeutic potential of an anaplastic lymphoma kinase inhibitor, LDK378, in cecal ligation and puncture (CLP)‐induced polymicrobial sepsis and examined its effects on the recruitment of MDSCs. LDK378 significantly improved the survival of CLP‐induced polymicrobial septic mice, which was paralleled by reduced organ injury, decreased release of inflammatory cytokines and decreased recruitment of MDSCs to the spleen. Importantly, LDK378 inhibited the migration of MDSCs to the spleen by blocking the CLP‐mediated upregulation of CC chemokine receptor 2 (CCR2), a chemokine receptor critical for the recruitment of MDSCs. Mechanistically, LDK378 treatment blocked the CLP‐induced CCR2 upregulation of MDSCs via partially inhibiting the phosphorylation of p38 and G‐protein‐coupled receptor kinase‐2 (GRK2) in bone marrow MDSCs of septic mice. Furthermore, in vitro experiments also showed that lipopolysaccharide (LPS)‐induced migration of MDSCs was similarly owing to the activation of GRK2 and upregulation of CCR2 by LPS, whereas the treatment with LDK378 partially blocked the LPS‐induced phosphorylation of p38 and GRK2 and decreased the expression of CCR2 on the cell surface, therefore leading to the suppression of MDSC migration. Together, these findings unravel a novel function of LDK378 in the host response to infection and suggest that LDK378 could be a potential therapeutic agent for sepsis. See also: News and Commentary by Patil

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Taurodeoxycholate Increases the Number of Myeloid-Derived Suppressor Cells That Ameliorate Sepsis in Mice

Cited by 47 publications

References 79 publications

X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure

X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure

Innate Priming of Neutrophils Potentiates Systemic Multiorgan Injury

LDK378 inhibits the recruitment of myeloid‐derived suppressor cells to spleen via the p38–GRK2–CCR2 pathway in mice with sepsis

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