Prioritization of Competing Damage and Developmental Signals by Migrating Macrophages in the Drosophila Embryo

Abstract

The function of immune cells is critically dependent on their capacity to respond to a complex series of navigational cues that enable them to home to various organ sites in the body or to respond to inflammatory cues such as those released at sites of tissue damage. From early embryonic stages, immune cells are faced with a barrage of signals that will not all be directing the cell to do the same thing. Here we use the Drosophila embryo to investigate how hemocytes (Drosophila macrophages), are able to prioritize key guidance signals and ignore others so that they are not pulled every which way. We identify the immediate wound attractant signal as H(2)O(2) and investigate how Drosophila macrophages respond to competing guidance cues-those emanating from a wound-versus standard developmental guidance cues, as well as those signals drawing cells toward neighboring dying cells. We reveal a hierarchy of responsiveness to attractant cues that varies over time and we identify why there is a wound refractile period early in embryonic development when macrophages cannot be distracted from their developmental migratory pathway to a site of tissue damage.

Macrophages and CSF-1

“…Indeed, the inflammatory activation of macrophages during development not only contributes to tissue damage and disruption of organ development through pro-inflammatory injury, but may also skew macrophages away from their trophic functions. 111,139,140 Inflammatory activation of fetal lung macrophages through NF-κB signaling was found to upregulate proinflammatory mediators such as IL-1β and alter expression of Wnt7b, bone morphogenic protein (BMP)4 111 and fibroblast growth factor (FGF)-10. 139 And while inflammatory challenges such as lipopolysaccharide (LPS) or IL-1β administration in models of chorioamnionitis promote accelerated maturation, the mechanism is distinct from alveolarisation, characterized by a lung pathology associated with BPD.…”

β-arrestin control of late endosomal sorting facilitates decoy receptor function and chemokine gradient formation

“…For instance, a migrating macrophage might have to direct its response in a field of cues that includes attraction signals originating from a wound, developmental guidance cues and signals emanating from apoptotic cells (Moreira et al, 2010). The potency of each of these competing signals depends, at least in part, on the absolute available level of the attractant.…”

Epithelial delamination and migration

“…Knockdown of this gradient with the drug diphenyleneiodonium (DPI), which inactivates the NADPH oxidases responsible for generating H 2 O 2 , blocks the wound inflammatory response. 21 Similarly, using a combination of genetic and pharmacological approaches Moreira and collaborators identified H 2 O 2 as the chemoattractant that guides Drosophila hemocytes toward a wound 22 ( Fig. 1).…”

“…In the attempt to eliminate the transformed cells, the immune system selects variants of them better suited to survive in the immunologically activated Embryonic hemocytes fail to migrate efficiently toward the wounded site in animals with reduced Duox-the enzyme responsible for H 2 O 2 production 23 -specifically within the embryonic epidermis. 22 H 2 O 2 production in vivo was monitored in control and Duox mutant embryos through the injection of a fluorochrome (acetyl-pentafluorobenzene sulphonyl fluorescein) that is normally converted into its fluorescent form when exposed to H 2 O 2 . In the same study, Moreira and collaborators illustrated that, similar to vertebrate embryos, 24 there is a refractive period where macrophages cannot be deviated from their developmental migratory routes to a site of tissue damage.…”

“…This suggests a hierarchy for the interpretation of different chemotactic cues by the macrophages in vivo. 22 In this period of non-responsiveness to wound signals embryonic tissues can still repair and they do so generally without producing scarring or fibrosis, suggesting the intriguing idea that scars are the result of the inflammatory process that takes place at the adults wounds. 25 Beyond their roles in the embryo, Drosophila hemocytes play an important role in efficiently fighting infections 26 and repairing tissue damage [27][28][29] during the larval and adult stages of the fly.…”