Abstract
Damage-associated molecular patterns (DAMPs) are molecules released by dead cells that trigger sterile inflammation and, in vertebrates, adaptive immunity. Actin is a DAMP detected in mammals by the receptor, DNGR-1, expressed by dendritic cells (DCs). DNGR-1 is phosphorylated by Src-family kinases and recruits the tyrosine kinase Syk to promote DC cross-presentation of dead cell-associated antigens. Here we report that actin is also a DAMP in invertebrates that lack DCs and adaptive immunity. Administration of actin to Drosophila melanogaster triggers a response characterised by selective induction of STAT target genes in the fat body through the cytokine Upd3 and its JAK/STAT-coupled receptor, Domeless. Notably, this response requires signalling via Shark, the Drosophila orthologue of Syk, and Src42A, a Drosophila Src-family kinase, and is dependent on Nox activity. Thus, extracellular actin detection via a Src-family kinase-dependent cascade is an ancient means of detecting cell injury that precedes the evolution of adaptive immunity.
Highlights
Trauma, burns, ischemia, strenuous exercise, all induce a sterile inflammatory response
To test whether actin might act as a Damage-associated molecular patterns (DAMPs) in Drosophila, we injected w1118 adult flies with actin or with buffer alone and carried out RNAseq gene expression profiling of total fly extracts (Figure 1a)
While we have learned much about the pathways that trigger inflammation in response to pathogen invasion (Medzhitov, 2010; Takeuchi and Akira, 2010), we still understand relatively little about induction of sterile inflammation following tissue injury (Rock et al, 2010)
Summary
Burns, ischemia, strenuous exercise, all induce a sterile inflammatory response. It is likely that this response evolved to clear cell debris, promote tissue repair and maintain tissue sterility (Zelenay and Reis e Sousa, 2013; Eming et al, 2014) but, if uncontrolled, it can lead to (aseptic) shock and, in some cases, death (Rock et al, 2010). The prevailing notion is that sterile inflammation is initiated by pro-inflammatory signals that are released by damaged cells. These include intracellular components that are exposed when cells lose their membrane integrity, such as ATP, uric
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