Editors' ChoiceSepsis

Putting the Brakes on Inflammation to Control Sepsis

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Science Translational Medicine  23 Apr 2014:
Vol. 6, Issue 233, pp. 233ec73
DOI: 10.1126/scitranslmed.3009254

More than 500,000 people in the United States acquire sepsis each year, and 40% of them die, at a cost of $16 billion. Difficult to diagnose and treat, sepsis is typically caused by blood-borne infections that induce a wave of systemic inflammation. This acute inflammatory response can have devastating consequences to host tissues, leading to organ failure and subsequent death. None of the numerous phase 3 clinical trials testing potential single-target therapies has resulted in a viable treatment. Now, a report by Zhang et al. suggests that targeting a broad array of inflammatory pathways might have a greater likelihood of success. They show that vascular endothelial growth factor receptor-3 (VEGFR-3), best known for regulating lymphangiogenesis, and its ligand VEGF-C are protective during sepsis, in which they slow down multiple sepsis-related inflammatory processes.

In 20 septic patients, VEGF-C levels were markedly increased in serum, whereas VEGF-C was barely detectable in healthy controls, making this molecule a candidate biomarker for sepsis. Mice in which VEGF-C was prevented from binding to its receptor VEGFR-3 became highly susceptible to sepsis. They exhibited uncontrolled expression of the key inflammatory cytokines interleukin 6 (IL-6), tumor necrosis factor–α (TNF-α), and IL-1β and the chemokines CCL2 and CXCL10. In the absence of VEGF-C signaling, nuclear factor κB (NF-κB), a crucial transcription factor that induces these genes, was activated, demonstrating that VEGF-C normally constrains NF-κB activity. Elaborated from the same cells that express the potentially damaging inflammatory cytokines, VEGF-C represents a self-control mechanism to prevent uncontrolled inflammation. The elevated VEGF-C expression in septic patients is likely not sufficient to control the inflammatory response. Collectively, these experiments show that the VEGFR-3–VEGF-C axis is induced in response to bacterial cues and that it acts to down-regulate inflammation and modify not just one, but multiple pathways that can cause tissue-damaging immune responses.

Boosting the strength of this signaling pathway with drugs could help to keep out-of-control cytokines and chemokines in check during sepsis. Because organ failure from overzealous immune responses can lead to death before antibiotics can control infection, infusion of VEGF-C could prolong patient survival by providing a larger time window for antibiotics to work. VEGF-C signaling is a naturally evolved system, designed to fine-tune and reduce inflammatory responses. Unlike current treatment regimes, therefore, it would not leave the patient immunocompromised. Putting the brakes on inflammation may be better than completely crippling it.

Y. Zhang et al., Activation of vascular endothelial growth factor receptor-3 in macrophages restrains TLR4-NF-κB signaling and protects against endotoxin shock. Immunity 40, 501–514 (2014). [Abstract]

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