CXCR4 blockade decreases CD4+ T cell exhaustion and improves survival in a murine model of polymicrobial sepsis

Abstract

Sepsis is a dysregulated systemic response to infection involving many inflammatory pathways and the induction of counter-regulatory anti-inflammatory processes that results in a state of immune incompetence and can lead to multi-organ failure. CXCR4 is a chemokine receptor that, following ligation by CXCL12, directs cells to bone marrow niches and also plays an important role in T cell cosignaling and formation of the immunological synapse. Here, we investigated the expression and function of CXCR4 in a murine model of polymicrobial sepsis. Results indicate that CXCR4 is selectively upregulated on naïve CD4+ and CD8+ T cells and CD4+ central memory T cells following the induction of sepsis, and that CXCR4 antagonism resulted in a significant decrease in sepsis-induced mortality. We probed the mechanistic basis for these findings and found that CXCR4 antagonism significantly increased the number of peripheral CD4+ and CD8+ T cells following sepsis. Moreover, mice treated with the CXCR4 antagonist contained fewer PD-1+ LAG-3+ 2B4+ cells, suggesting that blockade of CXCR4 mitigates CD4+ T cell exhaustion during sepsis. Taken together, these results characterize CXCR4 as an important pathway that modulates immune dysfunction and mortality following sepsis, which may hold promise as a target for future therapeutic intervention in septic patients.

Preexisting malignancy abrogates the beneficial effects of CXCR4 blockade during sepsis

“…Given our previous results demonstrating the up‐regulation of CXCR4 on immune cells in (PH) animals following sepsis, we hypothesized that CLP would also induce CXCR4 up‐regulation in mice with preexisting malignancy. To test this hypothesis, we utilized our previously published model in which naïve B6 mice are injected with a lung cancer cell line in the thigh and develop malignancy over the course of a 3‐week period.…”

“…As discussed above, we have previously published that CXCR4 antagonism with AMD3100 is an effective treatment to reduce mortality following CLP in PH C57BL/6 mice. Specifically, we found that 5 mg/kg AMD3100 administered at 1 h post CLP resulted in survival improvement from 20% to 65% . To explore the possibility that sepsis survival in cancer hosts could be improved by targeting CXCR4, AMD3100 was given at 1 h post CLP and the same volume of PBS was given to another group of cancer septic mice as a control.…”

“…CXCR4 is widely expressed on many different cell lineages and inhibition of CXCR4/CXCL12 signaling results in the release of these cells into the circulation, increasing peripheral absolute cell counts . Our previously published data demonstrated that CXCR4 was up‐regulated on T cells in mouse models of sepsis . Moreover, a previous study of human septic patients also revealed that CXCL12 levels were higher in patients with severe sepsis/septic shock as compared to healthy subjects .…”

“…Sham animals underwent laparotomy alone. Per previously published work, a 1 cm incision was made in the midline of the abdomen and cecum was ligated at 1 cm from the end with 4‐0 surgical suture. The ligated cecum was perforated by a through‐and‐through puncture (generating two individual punctures) with a 25‐gauge needle and stool was extruded.…”

“…By blocking CXCL12 activity, which significantly reduced BM release of granulocytes, they demonstrated that changes in the pattern of CXCL12 signaling are essential for neutrophil BM mobilization during sepsis. In addition, we recently showed that administration of AMD3100 (plerixafor), a CXCR4‐antagonist that is approved by the FDA for stem cell mobilization prior to autologous BM transplantation, abrogated the loss of peripheral T cells during sepsis, mitigated CD4 + T cell exhaustion during sepsis, and resulted in a significant decrease in sepsis‐induced mortality in PH mice . These findings suggest that redirecting functional cells out of the BM may be beneficial in sepsis.…”