A Possible Mechanism for Feedback Control in Joint Inflammation
Arthritis is a chronic inflammatory disease. In the early stages of the inflammatory response, neutrophils accumulate in the joint and release chemical mediators that promote inflammation. Physiologic mechanisms that down regulate this inflammatory response are poorly understood. Migration of neutrophils to sites of inflammation is dependent, in part, on adhesion to blood vessels via a molecule call L-selectin. Mechansims that cause shedding of L-selectin from neutrophils could result in a reduction of migration and consequently, in inflammation in the joint.
Levine, et al (Nature Medicine 5:1057, 1999) investigated the role of shedding of the leukocyte adhesion molecule, L-selectin, in downregulating arthritis induced by bradykinin. Using an in vivo rat model, they demonstrated that painful stimulation of sensory nerve fibers in the hindpaw produced a rapid inhibition of inflammation in the knee joint. They then showed that this remote inhibition of inflammation was mediated by the shedding of L-selectin from circulating neutrophils in vivo. Rats treated with a monoclonal antibody to L-selectin showed a profound decrease in bradykinin-induced inflammation.
Editorial comment: This is a fascinating study which shows that pain in one area, such as that induced by trauma or inflammation, activates an endogenous feedback circuit that systemically downregulates inflammatory responses in another. One mechanism for this downregulation appears to be shedding of L-selectin. Failure of this mechanism may contribute to the pathogenesis of chronic inflammatory diseases.
