Abstract
Sterile tissue injury is accompanied by an acute inflammatory response whereby innate immune cells rapidly migrate to the site of injury guided by pro-inflammatory chemotactic damage signals released at the wound. Understanding this immune response is key to improving human health, and recent advances in imaging technology have allowed researchers using different model organisms to observe this inflammatory response in vivo. Over recent decades, offering a unique combination of live time-lapse microscopy and genetics, the fruit fly Drosophila has emerged as a powerful model system to study inflammatory cell migration within a living animal.1–4 However, we still know relatively little regarding the identity of the earliest signals that drive this immune cell recruitment and the mechanisms by which they act within the complex, in vivo setting of a multicellular organism. Here, we couple the powerful genetics and live imaging of Drosophila with mathematical modeling to identify the fly complement ortholog—macroglobulin complement-related (Mcr)—as an
early, wound-induced chemotactic signal responsible for the inflammatory recruitment of immune cells to injury sites in vivo. We show that epithelial-specific knockdown of Mcr suppresses the recruitment of macrophages to wounds and combine predictive mathematical modeling with in vivo genetics to understand
macrophage migration dynamics following manipulation of this chemoattractant. We propose a model whereby Mcr operates alongside hydrogen peroxide to ensure a rapid and efficient immune response to damage, uncovering a novel function for this protein that parallels the chemotactic role of the complement component C5a in mammals.
early, wound-induced chemotactic signal responsible for the inflammatory recruitment of immune cells to injury sites in vivo. We show that epithelial-specific knockdown of Mcr suppresses the recruitment of macrophages to wounds and combine predictive mathematical modeling with in vivo genetics to understand
macrophage migration dynamics following manipulation of this chemoattractant. We propose a model whereby Mcr operates alongside hydrogen peroxide to ensure a rapid and efficient immune response to damage, uncovering a novel function for this protein that parallels the chemotactic role of the complement component C5a in mammals.
| Original language | English |
|---|---|
| Journal | Current Biology |
| Early online date | 18 Mar 2025 |
| DOIs | |
| Publication status | Published - 18 Mar 2025 |
Bibliographical note
For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) license to any author-accepted manuscript version arising from this submission.Data Availability Statement
All data reported in this paper will be shared by the lead contact upon request.Codes are available at https://github.com/Schumacher-group/ImmuneCellMigrationAnalysis.
Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
Acknowledgements
We would like to thank FlyBase25 as well as Bloomington Stock Center (University of Indiana, NIH P40OD018537) and the Vienna Drosophila Resource Center26 for providing Drosophila lines. The study would not have been possible without the critical work of H. Falconer (University of Edinburgh). We would also like to thank all members of the Wood lab and the Edinburgh Cell Death Collective (ECDC) as well as Dr. J. Houston for insightful discussion.Funding
This work is funded by a Wellcome Trust Investigator Award to W.W. (22460/Z/21/Z) and an MRC Programme grant (MR/W019264/1) to W.W., S.J.J., and C.D.L., as well as an Academy of Medical Sciences/Wellcome Trust/Gvmnt DBEIS/BHF/Diabetes UK Springboard Award (SBF003/1170) to L.J.S.
