Extracellular CIRP dysregulates macrophage bacterial phagocytosis in sepsis

Zhou, Mian; Aziz, Monowar; Yen, Hao-Ting; Ma, Gaifeng; Murao, Atsushi; Wang, Haichao

doi:10.1038/s41423-022-00961-3

Cited by 22 publications

(16 citation statements)

References 48 publications

(95 reference statements)

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“…Infection is the major factor which directly causes death after radiation ( 3 , 4 ). We have recently shown that eCIRP suppresses macrophage bacterial phagocytosis by STAT3 phosphorylation followed by the formation of STAT3-βPIX complex, which leads to Rac-1 inhibition ( 29 ). Even though the role of TREM-1 was not assessed in that study, upregulation of TREM-1 by eCIRP after radiation exposure may impair the phagocytic function of macrophages, considering the involvement of the eCIRP-TREM-1 axis reported in different settings.…”

Section: Discussionmentioning

confidence: 99%

Radiation upregulates macrophage TREM-1 expression to exacerbate injury in mice

Yamaga

Murao

et al. 2023

Front. Immunol.

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IntroductionExposure to high-dose ionizing radiation causes tissue injury, infections and even death due to immune dysfunction. The triggering receptor expressed on myeloid cells-1 (TREM-1) has been demonstrated to critically amplify and dysregulate immune responses. However, the role of TREM-1 in radiation injury remains unknown. Extracellular cold-inducible RNA-binding protein (eCIRP), a new damage-associated molecular pattern, is released from activated or stressed cells during inflammation. We hypothesized that ionizing radiation upregulates TREM-1 expression via eCIRP release to worsen survivalMethodsRAW264.7 cells and peritoneal macrophages collected from C57BL/6 wild-type (WT) mice were exposed to 5- and 10-Gray (Gy) radiation. C57BL/6 WT and CIRP-/- mice underwent 10-Gy total body irradiation (TBI). TREM-1 expression on RAW264.7 cells and peritoneal macrophages in vitro and in vivo were evaluated by flow cytometry. eCIRP levels in cell culture supernatants and in peritoneal lavage isolated from irradiated mice were evaluated by Western blotting. We also evaluated 30-day survival in C57BL/6 WT, CIRP-/- and TREM-1-/- mice after 6.5-Gy TBI.ResultsThe surface protein and mRNA levels of TREM-1 in RAW264.7 cells were significantly increased at 24 h after 5- and 10-Gy radiation exposure. TREM-1 expression on peritoneal macrophages was significantly increased after radiation exposure in vitro and in vivo. eCIRP levels were significantly increased after radiation exposure in cell culture supernatants of peritoneal macrophages in vitro and in peritoneal lavage in vivo. Moreover, CIRP-/- mice exhibited increased survival after 6.5-Gy TBI compared to WT mice. Interestingly, TREM-1 expression on peritoneal macrophages in CIRP-/- mice was significantly decreased compared to that in WT mice at 24 h after 10-Gy TBI. Furthermore, 30-day survival in TREM-1-/- mice was significantly increased to 64% compared to 20% in WT mice after 6.5-Gy TBI.ConclusionOur data indicate that ionizing radiation increases TREM-1 expression in macrophages via the release of eCIRP, and TREM-1 contributes to worse survival after total body irradiation. Thus, targeting TREM-1 could have the potential to be developed as a novel medical countermeasure for radiation injury.

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Section: Discussionmentioning

confidence: 99%

Radiation upregulates macrophage TREM-1 expression to exacerbate injury in mice

Yamaga

Murao

et al. 2023

Front. Immunol.

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“…We have found that eCIRP, a critical DAMP, causes apoptosis inhibition and aging in neutrophils and demonstrated that eCIRP is the major, if not only, factor to inhibit neutrophil apoptosis and increase aged neutrophils in sepsis by using CIRP −/− mice. Considering that eCIRP circulates systemically, as evidenced by elevated levels in the blood during sepsis (7,36), aged neutrophils may be generated not only within the microenvironment but also in the circulation or remote organs. We have previously found that CIRP −/− mice were protected from multiple organ injuries and exhibited improved survival in sepsis (7,36).…”

Section: Discussionmentioning

confidence: 99%

Extracellular Cirp Inhibits Neutrophil Apoptosis to Promote Its Aging by Upregulating Serpinb2 in Sepsis

Shimizu,

Murao,

Aziz

et al. 2023

Shock

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Background Sepsis reduces neutrophil apoptosis. As the result, neutrophils may become aged, exacerbating inflammation and tissue injury. Extracellular cold-inducible RNA-binding protein (eCIRP) acts as a damage-associated molecular pattern to promote inflammation and tissue injury in sepsis. SerpinB2, a serine protease inhibitor, has been shown to inhibit apoptosis. We hypothesize that eCIRP upregulates SerpinB2 to promote aged neutrophil subset by inhibiting apoptosis in sepsis. Methods We stimulated bone marrow-derived neutrophils (BMDNs) of wild-type (WT) mice with 1 μg/mL of recombinant mouse CIRP (i.e., eCIRP) and assessed cleaved caspase-3 and SerpinB2 by Western blotting. Apoptotic neutrophils were assessed by Annexin V/PI. BMDNs were stimulated with 1 μg/mL eCIRP and treated with or without PAC-1 (caspase-3 activator) and aged neutrophils (CXCR4hiCD62Llo) were assessed by flow cytometry. To induce sepsis, we performed cecal ligation and puncture (CLP) in WT or CIRP-/- mice. We determined the percentage of aged neutrophils and SerpinB2+ neutrophils in blood and spleen by flow cytometry. Results We found that cleaved caspase-3 levels were increased at 4 h of PBS treatment compared to 0 h, but decreased by eCIR P treatment. eCIRP reduced apoptotic cells after 20 h of treatment. eCIRP also increased the frequencies of aged neutrophils compared to PBS after 20 h, while PAC-1 treatment reduced aging in eCIRP-treated BMDNs. eCIRP significantly increased the expression of SerpinB2 at protein levels in BMDNs at 20 h. In WT mice, the frequencies of aged and SerpinB2+ neutrophils in blood and spleen were increased after 20 h of CLP, while in CIRP-/- mice, aged and SerpinB2+ neutrophils were significantly decreased compared to WT mice. We also found that aged neutrophils expressed significantly higher levels of SerpinB2 compared to non-aged neutrophils. Conclusions eCIRP inhibits neutrophil apoptosis to increase aged phenotype by increasing SerpinB2 expression in sepsis. Thus, targeting eCIRP could be a new therapeutic strategy to ameliorate inflammation caused by neutrophil aging in sepsis.

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“…CIRBP is induced by multiple external stimuli, including infection, hypoxia, hypothermia, and ultraviolet radiation, and it acts as a DAMP molecule that aggravates the inflammatory response 124,125 . Several studies have demonstrated that increased expression of CIRBP in the plasma predicts the poor prognosis of patients with sepsis 126,127 . In addition, it has been reported that increased expression of CIRBP can induce the expression of inflammatory cytokines by activating the NF‐kB and ERK signaling pathways 128–130 .…”

Section: Potential Role Of Rna Binding Proteins In Intervertebral Dis...mentioning

confidence: 99%

Emerging roles of RNA binding proteins in intervertebral disc degeneration and osteoarthritis

Li,

Gao

et al. 2023

Orthopaedic Surgery

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The etiology of intervertebral disc degeneration (IDD) and osteoarthritis (OA) is complex and multifactorial. Both predisposing genes and environmental factors are involved in the pathogenesis of IDD and OA. Moreover, epigenetic modifications affect the development of IDD and OA. Dysregulated phenotypes of nucleus pulposus (NP) cells and OA chondrocytes, including apoptosis, extracellular matrix disruption, inflammation, and angiogenesis, are involved at all developmental stages of IDD and OA. RNA binding proteins (RBPs) have recently been recognized as essential post‐transcriptional regulators of gene expression. RBPs are implicated in many cellular processes, such as proliferation, differentiation, and apoptosis. Recently, several RBPs have been reported to be associated with the pathogenesis of IDD and OA. This review briefly summarizes the current knowledge on the RNA‐regulatory networks controlled by RBPs and their potential roles in the pathogenesis of IDD and OA. These initial findings support the idea that specific modulation of RBPs represents a promising approach for managing IDD and OA.

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Extracellular CIRP dysregulates macrophage bacterial phagocytosis in sepsis

Cited by 22 publications

References 48 publications

Radiation upregulates macrophage TREM-1 expression to exacerbate injury in mice

Radiation upregulates macrophage TREM-1 expression to exacerbate injury in mice

Extracellular Cirp Inhibits Neutrophil Apoptosis to Promote Its Aging by Upregulating Serpinb2 in Sepsis

Emerging roles of RNA binding proteins in intervertebral disc degeneration and osteoarthritis

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