Neutrophils scan for activated platelets to initiate inflammation

Abstract

Immune and inflammatory responses require leukocytes to migrate within and through the vasculature, a process that is facilitated by their capacity to switch to a polarized morphology with asymmetric distribution of receptors. We report that neutrophil polarization within activated venules served to organize a protruding domain that engaged activated platelets present in the bloodstream. The selectin ligand PSGL-1 transduced signals emanating from these interactions, resulting in redistribution of receptors that drive neutrophil migration. Consequently, neutrophils unable to polarize or to transduce signals through PSGL-1 displayed aberrant crawling, and blockade of this domain protected mice against thrombo-inflammatory injury. These results reveal that recruited neutrophils scan for activated platelets, and suggest that their bipolarity allows integration of signals present at both the endothelium and the circulation before inflammation proceeds.

Neutrophil infiltration to the brain is platelet‐dependent, and is reversed by blockade of platelet GPIbα

“…These data replicate findings from Sreeramkumar et al .,3 where only LPS plus an anti MHC‐I antibody produced a strong enough lung inflammation to be attenuated by platelet intervention, as LPS‐induced inflammation alone was unaffected by blocking of platelet activity. Together, these findings provide further evidence for tissue‐specific‐mechanisms of innate immunity and highlight the flexibility of the lungs in dealing with pathogen‐driven inflammation.…”

“…Indeed, neutrophils have neurotoxic effects on neurons in vitro ,16 an effect that appears dependent on phenotypic changes that occur during neutrophil cerebrovascular infiltration 17. Targeting various aspects of platelet activation reduces stroke injury 3, 14, 18. This, together with platelet‐dependent neutrophil infiltration mechanisms3 and the relevance of these in different tissues shown here, suggests that platelet‐targeted therapies may be beneficial after CNS injury.…”

“…However, Sreeramkumar and co‐workers recently described platelet–neutrophil dynamics in inflamed cremaster blood vessels, showing that platelets are key to initiating the process of neutrophil tethering, rolling and crawling upon vessels 3. To determine if platelets are required to drive innate immune responses in other tissues we stimulated inflammation with the bacterial endotoxin LPS in mice with a reduction in platelets.…”

“…However, prolonged or excessive neutrophil‐mediated inflammation is injurious to adjacent healthy tissue in many situations, and is especially harmful during central nervous system (CNS) inflammation where capacity for repair is limited 2. An interaction with platelets is essential to trigger the tethering and rolling of neutrophils on inflamed venules, before their extravasation 3. Activated platelets attach to neutrophils via the release and surface expression of platelet P‐selectin from α ‐granules, which binds to P‐selectin glycoprotein ligand‐1 expressed on neutrophils 4.…”

Neutrophil derived CSF1 induces macrophage polarization and promotes transplantation tolerance

“…Future experiments are aimed at elucidating the mechanisms by with anti-CD40L mAb promote “tolerogenic” neutrophils. In this respect we hypothesize neutrophils scanning for platelets (35) may receive a “tolerogenic” signal following CD40L blockade in activated platelets (36) that may lead to CSF1 production and transplantation tolerance under sterile inflammatory conditions.…”