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

Abstract

Although the inflammatory response is essential for protecting tissues from injury and infection, 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 extravasation, 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-selectin. This adhesion is prevented when L-selectin is shed from the neutrophil membrane. Although shedding of L-selectin is recognized as a potentially important mechanism for regulating neutrophils, 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.

Omega 3 (n−3) fatty acids down-regulate nuclear factor-kappa B (NF-κB) gene and blood cell adhesion molecule expression in patients with homozygous sickle cell disease

“…L-selectin (CD62L) facilitates rolling and temporary arrest of circulating leukocytes on endothelium surface [53], whereas β2-integrin (CD11b) is involved in subsequent stable adhesion [54,55]. Therefore, therapeutic approaches to reduce expression of CD62L and CD11B have been important strategies to prevent vaso-occlusion in sickle cell disease [50].…”

Frontline: Inhibition of allergen‐induced pulmonary inflammation by the tripeptide feG: a mimetic of a neuro‐endocrine pathway

“…The increased expression of adhesion molecules on the surface of BAL-derived leukocytes may be important in cell communication and activation, and account for functional differences between BAL-derived and peripheral blood cells. Entry of PMN into inflamed tissue requires L-and P-selectin activity [16], and increased CD62L shedding has been suggested to have inhibitory effects on PMN adhesion and transmigration across endothelium, thus reducing PMN recruitment [17]. Thus, down-regulation of CD62L on PMN by feG may have a role in reducing PMN numbers in the lungs of OVAchallenged rats.…”

A Potential Role for Annexin 1 as a Physiologic Mediator of Glucocorticoid-Induced L-Selectin Shedding from Myeloid Cells

“…L-selectin has been implicated in several steps during neutrophil recruitment to inflammatory sites: tethering and rolling of the neutrophil on the endothelium (49), neutrophilneutrophil interactions (50), activation of intracellular signaling pathways (51), and extravascular migration (52). Previous studies have shown that modulation of L-selectin levels via shedding can have a marked impact on neutrophil-endothelial interactions (16,53,54).…”

“…Several studies show that administration of glucocorticoids to humans and animals induces L-selectin shedding on peripheral blood neutrophils (11)(12)(13)(14). In addition, our previous work has shown that inhibition of L-selectin-dependent plasma extravasation is blocked by both adrenalectomy and a glucocorticoid synthesis inhibitor (15,16). However, when neutrophils are treated in vitro with doses of glucocorticoids that produce L-selectin shedding in vivo, shedding is not observed (17)(18)(19).…”