DNA damage signaling in Drosophila macrophages modulates systemic cytokine levels in response to oxidative stress
Fabian Hersperger,
Tim Meyring,
Pia Weber,
Chintan Chhatbar,
Gianni Monaco,
Marc S Dionne,
Katrin Paeschke,
Marco Prinz,
Olaf Groß,
Anne-Kathrin Classen,
Katrin Kierdorf
Affiliations
Fabian Hersperger
Institute of Neuropathology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany
Tim Meyring
Institute of Neuropathology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
Pia Weber
Institute of Neuropathology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
Chintan Chhatbar
Institute of Neuropathology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
Gianni Monaco
Institute of Neuropathology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; Institute for Transfusion Medicine and Gene Therapy, Medical Center-University of Freiburg, Freiburg, Germany
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom; Department of Life Sciences, Imperial College London, London, United Kingdom
Department of Oncology, Haematology and Rheumatology, University Hospital Bonn, Bonn, Germany; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
Marco Prinz
Institute of Neuropathology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
Olaf Groß
Institute of Neuropathology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
Hilde-Mangold-Haus, Faculty of Biology, University of Freiburg, Freiburg, Germany; CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
Institute of Neuropathology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg, Germany; CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
Environmental factors, infection, or injury can cause oxidative stress in diverse tissues and loss of tissue homeostasis. Effective stress response cascades, conserved from invertebrates to mammals, ensure reestablishment of homeostasis and tissue repair. Hemocytes, the Drosophila blood-like cells, rapidly respond to oxidative stress by immune activation. However, the precise signals how they sense oxidative stress and integrate these signals to modulate and balance the response to oxidative stress in the adult fly are ill-defined. Furthermore, hemocyte diversification was not explored yet on oxidative stress. Here, we employed high-throughput single nuclei RNA-sequencing to explore hemocytes and other cell types, such as fat body, during oxidative stress in the adult fly. We identified distinct cellular responder states in plasmatocytes, the Drosophila macrophages, associated with immune response and metabolic activation upon oxidative stress. We further define oxidative stress-induced DNA damage signaling as a key sensor and a rate-limiting step in immune-activated plasmatocytes controlling JNK-mediated release of the pro-inflammatory cytokine unpaired-3. We subsequently tested the role of this specific immune activated cell stage during oxidative stress and found that inhibition of DNA damage signaling in plasmatocytes, as well as JNK or upd3 overactivation, result in a higher susceptibility to oxidative stress. Our findings uncover that a balanced composition and response of hemocyte subclusters is essential for the survival of adult Drosophila on oxidative stress by regulating systemic cytokine levels and cross-talk to other organs, such as the fat body, to control energy mobilization.
