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Painful stimulation suppresses joint inflammation by inducing shedding of L-selectin from neutrophils

Nature Medicine volume 5, pages 1057–1061 (1999)Cite this article

Abstract

Although the inflammatory response is essential for protecting tissues from injury and infection1, unrestrained inflammation can cause chronic inflammatory diseases such as arthritis, colitis and asthma. Physiological mechanisms that downregulate inflammation are poorly understood. Potent control might be achieved by regulating early stages in the inflammatory response, such as accumulation of neutrophils at the site of injury, where these cells release chemical mediators that promote inflammatory processes including plasma extravasation2, bacteriocide and proteolysis. To access an inflammatory site, neutrophils must first adhere to the vascular endothelium in a process mediated in part by the leukocyte adhesion molecule L-selectin3. This adhesion is prevented when L-selectin is shed from the neutrophil membrane4,5. Although shedding of L-selectin is recognized as a potentially important mechanism for regulating neutrophils4,5,6,7, its physiological function has not been demonstrated. Shedding of L-selectin may mediate endogenous downregulation of inflammation by limiting neutrophil accumulation at inflammatory sites. Here we show that activation of nociceptive neurons induces shedding of L-selectin from circulating neutrophils in vivo and that this shedding suppresses an ongoing inflammatory response by inhibiting neutrophil accumulation. These findings indicate a previously unknown mechanism for endogenous feedback control of inflammation. Failure of this mechanism could contribute to the etiology of chronic inflammatory disease.

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Figure 1: Noxious stimulation inhibits BK-induced knee joint plasma extravasation.
Figure 2: BK-induced knee joint plasma extravasation is neutrophil-dependent and noxious stimulation inhibits BK-induced neutrophil accumulation.
Figure 3: Blocking L-selectin inhibits BK-induced plasma extravasation; and noxious stimulation induces shedding of L-selectin and a concomitant decrease in neutrophil tethering and rolling.
Figure 4: Inhibitor of shedding blocks inhibition of BK-induced plasma extravasation induced by noxious stimulation.

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Acknowledgements

This work was supported by NIH-AM32624.

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Authors and Affiliations

  1. NIH Pain Center, UCSF, 521 Parnassus Avenue, San Francisco, 94143-0440, California, USA

    Holly J. Strausbaugh, Paul G. Green, Ernest Lo, David B. Reichling & Jon D. Levine

  2. Program in Biomedical Sciences, UCSF, 531 Parnassus Avenue, San Francisco, 94143-0444, California, USA

    Holly J. Strausbaugh, Steven D. Rosen & Jon D. Levine

  3. Department of Anatomy and Program in Immunology, UCSF, 531 Parnassus Avenue, San Francisco, 94143-0452, California, USA

    Kirsten Tangemann & Steven D. Rosen

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  1. Holly J. Strausbaugh
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Strausbaugh, H., Green, P., Lo, E. et al. Painful stimulation suppresses joint inflammation by inducing shedding of L-selectin from neutrophils. Nat Med 5, 1057–1061 (1999). https://doi.org/10.1038/12497

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