Animals have acquired the capacity to recognize signals called damage-associated molecular patterns (DAMPs). DAMPs are associated with tissue damage and wounding, and are involved in activating specific pathways involved in repair or in inflammation. Several DAMPs have been identified in mammals, which include cellular components such as ATP, uric acid, nucleic acids and actin cytoskeleton components. Nevertheless, the pathway and effector mechanisms that are activated by DAMPs and how these pathways are integrated with other facets of the innate immune response are poorly understood.
Drosophila melanogaster has emerged as a critical model for deciphering the molecular mechanisms on how signaling pathways respond to external stimuli.
The JAK/STAT pathway that is conserved from flies to mammals plays important roles in both immunity and repair, where its dysfunction can lead to diseases such as blood cancers and severely compromised immunodeficiency. Recently, a lot of work has shown the importance of this signalling response to protect flies by triggering repair programs in the intestine of flies through bacteria-induced stem cell proliferation.
When damage occurs in adult Drosophila, not only is there a local response of the injured tissue, but a coordinated action across different tissues is elicited to help the organism overcome the deleterious effect of an injury. On injury, in different model organisms there is a rapid production of H2O2 in response to wounding. Here, we show that hydrogen peroxide is required for the activation of Toll signaling and induction of the evolutionarily conserved cytokine, upd3, from hemocytes in Drosophila. We show that the NADPH oxidase Duox is required in hemocytes to increase levels of H2O2 and in the absence of hemocyte activation to this danger signal, flies show increased lethality on injury. We provide evidence that production of the cytokine Upd3 involves the accumulation of intracellular ROS in hemocytes, which is facilitated by the diffusion of hydrogen peroxide through a newly identified channel protein, Prip. Thus, levels of ROS inside hemocytes appear as a critical mechanism that regulates the inflammatory response of hemocytes.