American Society of Hematology

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Dendritic Cells Inflamed by Coagulation

By Robert Flaumenhaft, MD, PhD

2008-09-01

Dr. Flaumenhaft indicated no relevant conflicts of interest.

Niessen F, Schaffner F, Furlan-Freguia C, et al. Dendritic cell PAR1–S1P3 signaling couples coagulation and inflammation. Nature. 2008;452:654-8.

That crosstalk occurs between coagulation and inflammation during sepsis has been appreciated for decades. This link has been spotlighted with the use of activated protein C in sepsis therapy. Yet, a more detailed understanding of the coupling of coagulation and inflammation is required to identify superior strategies for treating decompensated inflammatory responses. Recent work by Niessen, et al. demonstrates that coupling of protease-activated receptor 1 (PAR1) signaling to the sphingosine-1-phosphate 3 (S1P3) receptor on dendritic cells provides a critical connection between coagulation and inflammation.

PAR1 is a thrombin receptor that becomes activated following tissue factor-initiated production of thrombin. The investigators found that delayed inflammatory responses and mortality from a 90 percent lethal dose of lipopolysaccharide (LPS) were significantly decreased in PAR1^-/- mice, by use of a direct thrombin inhibitor, or by a PAR1 antagonist. Based on previous studies linking PAR1 stimulation to sphingosine phosphate signaling,¹ the researchers evaluated the role of sphingosine kinase 1 (SphK1) and S1P3 in PAR1-mediated delayed inflammatory responses. Delayed inflammatory responses were diminished in SphK1^-/- and S1P3^-/- mice and could be restored in PAR1^-/- mice via stimulation of S1P3. These observations suggested that SphK1 and S1P3 acted as downstream effectors of PAR1.

The investigators' original hypothesis was that vascular cells mediated the effects of PAR1 stimulation in inflammation. Unexpectedly, reconstitution of PAR1^-/- mice with wild-type bone marrow restored normal, delayed inflammation. Multiplex cytokine profiles suggested that dendritic cells mediated the inflammatory response. Adaptive transfer of wild-type dendritic cells into PAR1^-/-, SphK1^-/-, or S1P3^-/- mice restored delayed inflammatory response and reversed the survival advantage to LPS challenge observed in these phenotypes. The observation that only wild-type dendritic cells (not PAR1^-/- or S1P3^-/-dendritic cells) were able to restore systemic inflammation demonstrated that PAR1 and S1P3 are coupled in an autocrine manner on dendritic cells.

The authors next analyzed local inflammation in mesenteric lymph nodes following intraperitoneal LPS administration. They found that loss of PAR1–S1P3 signaling resulted in increased dendritic cell sequestration in lymph nodes, consistent with previous data that S1P3 signaling enhances dendritic cell motility.^2,3 When PAR1–S1P3 signaling was disrupted, IL-1β levels increased in the lymph nodes but were reduced in blood and lung. Dendritic cells express tissue factor. Impairment of PAR1–S1P3 crosstalk resulted in increased fibrin deposition in lymph nodes and decreased peripheral thrombin-antithrombin following LPS challenge. These results indicated that PAR1–S1P3 signaling on dendritic cells mediates dissemination of inflammation and coagulation from draining lymph nodes to the lungs and periphery.

Severe sepsis affects more than 750,000 patients a year and is associated with a mortality of approximately 30 percent. Systemic inflammation and disseminated intravascular coagulation resulting from excessive activation of the innate immune system are hallmarks of sepsis. Yet, how the coagulation and immune systems interact to contribute to dissemination of the inflammatory response is poorly understood.

Niessen and colleagues uncovered an important component of this response. They found that stimulation of dendritic cells through PAR1 results in stimulation of SphK and S1P3 leading to systemic dissemination of inflammation and coagulation. Interruption of PAR1–S1P3 crosstalk prevents delayed systemic inflammation and confines the inflammatory response to the lymph nodes. Pharmacological blockade of PAR1 confers a substantial survival advantage following LPS challenge or caecal ligation and puncture. These studies identify a potential strategy to control systemic inflammation without compromising host defense.