The role of CXCL10 in the pathogenesis of experimental septic shock

Herzig, Daniela S; Luan, Liming; Bohannon, Julia K.; Toliver‐Kinsky, Tracy; Guo, Yin; Sherwood, Edward R.

doi:10.1186/cc13902

Cited by 36 publications

(30 citation statements)

References 53 publications

(82 reference statements)

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“…However, as shown in previous studies from our lab and others, NK cells participate in the propagation of acute inflammation and physiological dysfunctions in experimental models of polymicrobial peritonitis (31), endotoxin shock (32), pneumococcal pneumonia (33), systemic Escherichia coli and Streptococcus pyogenes infection (34, 35), and polytrauma (36). Our lab previously showed that NK cells quickly migrate to sites of infection during intraabdominal sepsis, in a manner regulated by the chemokines CXCL9 and CXCL10 (23, 37–39). During sepsis, activated NK cells increased production of IFN-γ, which is known to potentiate inflammation by activating macrophages, dendritic cells and other innate immune cells (31, 40).…”

Section: Discussionmentioning

confidence: 99%

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IL-15 Enables Septic Shock by Maintaining NK Cell Integrity and Function

Guo

Luan

Patil

et al. 2017

The Journal of Immunology

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Interleukin-15 (IL-15) is essential for development and differentiation of natural killer (NK) and memory (m)CD8+ T cells. Our lab previously showed that NK and CD8+ T lymphocytes facilitate the pathobiology of septic shock. However, factors that regulate NK and CD8+ T lymphocyte functions during sepsis are not well characterized. We hypothesized that IL-15 promotes the pathogenesis of sepsis by maintaining NK and mCD8+ T cell integrity. To test our hypothesis, the pathogenesis of sepsis was assessed in IL-15-deficient (IL-15 KO) mice. IL-15 KO mice showed improved survival, attenuated hypothermia, and less pro-inflammatory cytokine production during septic shock caused by cecal ligation and puncture (CLP) or endotoxin-induced shock. Treatment with IL-15 superagonist (IL-15 SA, IL-15/IL-15Rα complex) regenerated NK and mCD8+ T cells and re-established mortality of IL-15 KO mice during septic shock. Preventing NK cell regeneration attenuated the restoration of mortality caused by IL-15 SA. If given immediately prior to septic challenge, IL-15 neutralizing IgG M96 failed to protect against septic shock. However, M96 caused NK cell depletion if given 4 days prior to septic challenge and conferred protection. IL-15 SA treatment amplified endotoxin shock, which was prevented by NK cell or IFNγ depletion. IL-15 SA treatment also exacerbated septic shock caused by CLP when given after the onset of sepsis. In conclusion, endogenous IL-15 doesn’t directly augment the pathogenesis of sepsis but enables the development of septic shock by maintaining NK cell numbers and integrity. Exogenous IL-15 exacerbates the severity of sepsis by activating NK cells and facilitating IFNγ production.

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Section: Discussionmentioning

confidence: 99%

“…The protocol was described previously (23). In brief, mice were anesthetized with 2% isoflurane in oxygen.…”

Section: Methodsmentioning

confidence: 99%

IL-15 Enables Septic Shock by Maintaining NK Cell Integrity and Function

Guo

Luan

Patil

et al. 2017

The Journal of Immunology

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“…Natural killer cells rapidly migrate to sites of bacterial infection. CXCR3‐expressing NK cells quickly migrate from secondary lymphoid organs to the peritoneal cavity within 4–6 hr after the initiation of intra‐abdominal sepsis, in a manner regulated by the chemokines CXCL9 and CXCL10 . CXCR3 + NK cells are the murine equivalent of human CD56 bright NK cells, both of which produce significantly more IFN‐ γ than CXCR3 − CD56 dim NK cells .…”

Section: Nk Cells: Friend or Foe During Sepsis?mentioning

confidence: 99%

“…CXCR3-expressing NK cells quickly migrate from secondary lymphoid organs to the peritoneal cavity within 4-6 hr after the initiation of intra-abdominal sepsis, in a manner regulated by the chemokines CXCL9 and CXCL10. 90,91 CXCR3 + NK cells are the murine equivalent of human CD56 bright NK cells, both of which produce significantly more IFN-c than CXCR3 À CD56 dim NK cells. 92 Our laboratory subsequently performed phenotypic characterization of these CXCR3 + mouse NK cells in the context of sepsis.…”

Section: Detrimental Role Of Nk Cells During Experimental Sepsismentioning

confidence: 99%

The biology of natural killer cells during sepsis

et al. 2017

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SummaryNatural killer (NK) cells are large granular lymphocytes largely recognized for their importance in tumour surveillance and the host response to viral infections. However, as the major innate lymphocyte population, NK cells also coordinate early responses to bacterial infections by amplifying the antimicrobial functions of myeloid cells, especially macrophages, by production of interferon-c (IFN-c). Alternatively, excessive NK cell activation and IFN-c production can amplify the systemic inflammatory response during sepsis resulting in increased physiological dysfunction and organ injury. Our understanding of NK cell biology during bacterial infections and sepsis is mostly derived from studies performed in mice. Human studies have demonstrated a correlation between altered NK cell functions and outcomes during sepsis. However, mechanistic understanding of NK cell function during human sepsis is limited. In this review, we will review the current understanding of NK cell biology during sepsis and discuss the challenges associated with modulating NK cell function during sepsis for therapeutic benefit.

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“…Interferon (IFN)-γ-induced protein 10 (IP-10/CXCL10) appears to contribute to the pathogenesis of several diseases and has been suggested as a potential biomarker of viral infection1011, late-onset bacterial infection in premature infants12, and a promising biomarker of sepsis and septic shock1314. Combined analysis of IP-10 and IFN-γ has also been reported as a useful biomarker for diagnosis and monitoring therapeutic efficacy in patients with active tuberculosis151617, and both remain detectable in the urine of patients with pulmonary diseases in the absence of renal dysfunction18.…”

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Viral and bacterial co-infection in severe pneumonia triggers innate immune responses and specifically enhances IP-10: a translational study

Hoffmann

Machado

Terrier

et al. 2016

Sci Rep

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Mixed viral and bacterial infections are widely described in community-acquired pneumonia; however, the clinical implications of co-infection on the associated immunopathology remain poorly studied. In this study, microRNA, mRNA and cytokine/chemokine secretion profiling were investigated for human monocyte-derived macrophages infected in-vitro with Influenza virus A/H1N1 and/or Streptococcus pneumoniae. We observed that the in-vitro co-infection synergistically increased interferon-γ-induced protein-10 (CXCL10, IP-10) expression compared to the singly-infected cells conditions. We demonstrated that endogenous miRNA-200a-3p, whose expression was synergistically induced following co-infection, indirectly regulates CXCL10 expression by targeting suppressor of cytokine signaling-6 (SOCS-6), a well-known regulator of the JAK-STAT signaling pathway. Additionally, in a subsequent clinical pilot study, immunomodulators levels were evaluated in samples from 74 children (≤5 years-old) hospitalized with viral and/or bacterial community-acquired pneumonia. Clinically, among the 74 cases of pneumonia, patients with identified mixed-detection had significantly higher (3.6-fold) serum IP-10 levels than those with a single detection (P = 0.03), and were significantly associated with severe pneumonia (P < 0.01). This study demonstrates that viral and bacterial co-infection modulates the JAK-STAT signaling pathway and leads to exacerbated IP-10 expression, which could play a major role in the pathogenesis of pneumonia.

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The role of CXCL10 in the pathogenesis of experimental septic shock

Cited by 36 publications

References 53 publications

IL-15 Enables Septic Shock by Maintaining NK Cell Integrity and Function

IL-15 Enables Septic Shock by Maintaining NK Cell Integrity and Function

The biology of natural killer cells during sepsis

Viral and bacterial co-infection in severe pneumonia triggers innate immune responses and specifically enhances IP-10: a translational study

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