Neutrophils mediate edema formation but not mechanical allodynia during zymosan-induced inflammation

Abstract

Inflammatory pain is based on stimulation and sensitization of peripheral endings of sensory neurons (nociceptors) by pronociceptive mediators. These mediators can be released by resident cells, as well as invading immune cells. Although neutrophils are known to release various mediators, which can stimulate or sensitize nociceptors, the extent of their contribution to nociceptive responses is unclear. Here, we studied the contribution of neutrophils to zymosan-induced inflammatory pain, which is characterized by an early recruitment of high numbers of neutrophils. Surprisingly, antibody-mediated neutrophil depletion caused a complete loss of edema formation but had no effect on mechanical pain thresholds. Blockage of the interaction between neutrophils and platelets or endothelial cells using antibodies directed against CD11b and CD162 reduced neutrophil recruitment to the site of inflammation. Again, the treatment decreased zymosan-induced edemas without altering mechanical pain thresholds. Also, HLB-219 mice, which have five to 10 times less platelets than WT mice, showed reduced neutrophil recruitment to the site of inflammation and decreased edema sizes, whereas, again, mechanical thresholds were unaltered. The effects observed in HLB-219 mice were relatively small and not reproduced in vWF-deficient mice or after antibody-mediated blockage of GPIbα. Flow chamber and transmigration assays showed that platelets were not necessary for neutrophil adhesion to endothelial cells but increased their transmigration. Taken together, zymosan-induced mechanical allodynia is, in contrast to edema formation, independent of neutrophils, and recruitment of neutrophils is only partly influenced by interactions with platelets.

CD11b+Ly6G−myeloid cells mediate mechanical inflammatory pain hypersensitivity

“…Neutrophils secrete many proinflammatory mediators but also produce opioid peptides that might reduce pain. This dichotomy is evident in the literature, with studies showing that these cells can increase (53)(54)(55) or decrease (56, 57) hypersensitivity, whereas others have shown no effect (58,59) in various models of inflammatory pain. Our results suggest a lack of any major contribution for these cells to pain, at least under our conditions and in other models in which clear depletion was demonstrated.…”

von Willebrand factor and inflammation

“…In contrast, VWF deficiency was reported to result in a marked increase in BBB permeability in an experimental model for allergic encephalomyelitis, resulting in an increased infiltration of lymphocytes and monocytes . Finally, the extent of vascular permeability was shown to be fully independent of VWF in a model of zymosan‐induced inflammation . Thus, the extent of how VWF modulates vascular permeability may depend on the experimental model that is applied, although the majority of models point to VWF increasing vascular permeability.…”

Activated Platelets Induce an Anti-Inflammatory Response of Monocytes/Macrophages through Cross-Regulation of PGE2and Cytokines

“…At sites of injuries or infections, platelets are the first cells to be recruited to the vascular endothelium. There they interact with various cell types, including monocytes, neutrophils, and endothelial cells, and, thereby, regulate cellular adhesion and extravasation [3, 4]. Most platelet functions and their interactions with other cell types are restricted to events taking place within the blood vessels.…”