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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - IMMUNE CELL SWARMS (Innate Immune Cell Swarms: Integrating and Adapting Single Cell and Population Dynamics in Inflamed and Infected Tissues)

Teaser

Summary

The inflammatory response protects the body against infection and injury but can itself become dysregulated with deleterious consequences to the organism. As the key cell type for eliminating bacteria and fungi, neutrophils accumulate as one of the first inflammatory cells at local sites of tissue injury and infection. While studies in living organisms have identified many factors that guide neutrophil migration, we hardly understand how these cells integrate the plethora of signals arising in inflammatory environments and coordinate their dynamic behaviour with other tissue-resident immune cells. Recent intravital microscopy studies have discovered an unexpected phenomenon during this response: Swarm formation of neutrophils. It is now clear that intercellular communication among neutrophils amplifies their recruitment in a feed-forward manner, which contributes to their coordinated swarming response. However, the stop signals for neutrophil swarming have not been defined yet. It is completely unknown how the swarming response is terminated to avoid unlimited neutrophil accumulation and prevent excessive inflammation. The failure to shutdown these pro-inflammatory circuits is considered critical in non-healing wounds and at the onset of chronic inflammation, which in turn may contribute to degenerative diseases such as cancer, diabetes and autoimmune diseases. Hence, there is an urgent need for more detailed information to understand the molecular control of neutrophil swarm dynamics and their contribution to the delicate balance between host protection and tissue destruction in inflammatory and infectious diseases.

This project aims to systematically define the mechanisms controlling neutrophil swarming during the resolution phase of inflammation and infection. Do neutrophils self-limit their swarming response? What role does the local environment, in particular the secondary swarms of myeloid cells, play for the resolution of neutrophil swarms? Are there differences in swarm control between situations of sterile inflammation and infection? Currently we have little understanding of these issues. Learning about the functional interplay of self-limiting processes and active anti-inflammatory programs in controlling neutrophil accumulation in vivo, and will provide valuable knowledge about the molecular mechanisms used to resolve inflammation under physiological and pathophysiological conditions.

Work performed

We have finished our work programme on understanding how the balance of self-limiting processes and active anti-inflammatory programs shape neutrophil swarming dynamics under conditions of sterile inflammation and infection. The main results of this work are prepared for submission to peer-reviewed scientific journals and released upon publication.

Our concepts on leukocyte navigation developed from the study of neutrophil swarms are currently also compared to navigation strategies of other immune cell types. Our recent review â€žConcepts of GPCR-controlled navigation in the immune systemâ€œ (LÃ¤mmermann T & KastenmÃ¼ller W, Immunol Rev 2019, 289(1):205-231) provides a broad overview on the molecular mechanisms behind navigation strategies of several immune cell types.

Final results

From our studies on neutrophil swarms, we expect to uncover biological principles of swarming that might also underlie the collective migration patterns of other leukocytes. The long-term goal will be to expand our studies to other swarming immune cells and investigate if similar concepts of internal and external control mechanisms shape their dynamics during immune responses.