Institut Pasteur identifies metabolic ALARMIN factors mediating local-systemic innate immune communication

 Across metazoans, scaling the level of the tissue damage or pathogen invasion by the local immunity is a pivotal sensing and alarming step for the fine-tuned systemic immunity. Thus, interorgan communication is critical to help maintain the homeostasis of the local-systemic immunological crosstalk, which employs messenger factors such as damage-associated molecular patterns (DAMPs). Among these distress and damage-associated alert molecules, small molecular metabolites, such as purine metabolites (ATP and adenosine) and uric acid, are emerging as important alarmins of innate immunity. Immune activation is always tightly associated with metabolic reprogramming. However, the metabolites involved in sensing and alarming the immune response in remote organs are still poorly understood, due to the fact that the identification of these messenger metabolites and the understanding of their contribution to the spatiotemporal regulation of innate immune interorgan communications that underpin systemic immunity in vivo is often challenging.


Drosophila melanogaster (fruit fly) is a supreme organism to investigate interorgan communications due to the advantages of highly conserved signaling pathways, similar function of organ systems compared to those of humans, and powerful genetic tools. Professor Lei Pan from Institut Pasteur (IPS) of Chinese Academy of Sciences, in cooperation with his colleagues, followed their previous studied on the homeostatic regulation of intestinal IMD/Relish (TNFR/NF-κB in mammals) signaling (Nature Microbiology, 2017) and found that intestinal IMD activation locally sufficiently and sequentially triggers systemic IMD responses in hemocytes (equivalent to mammalian macrophages) and the fat body (equivalent to the liver in mammals). And GC-MS metabolomic analysis reveals that intestinal IMD activation causes the increase of sugar alcohols of polyol pathway in the hemolymph (equivalent to vertebrate peripheral blood). Then they identified fly Aldose reductase (dAR1) mediating polyol pathway (an alternative glucose metabolism pathway), and found that only dAR1 in hemocytes is required for this interorgan communication. Genetic and molecular studies further show that polyols in the hemolymph activate fat body IMD via Mmp2-mediated cleavage of PRGP-LC, the receptor of systemic immune signalling.


Therefore, this work has shown for the first time that AR in hemocytes is a sensor for the local IMD/TNF activation in the gut, and sorbitol then alerts the global IMD/TNF response in the fat body. Sorbitol thus may be a new carbohydrate alarmin that triggers the systemic immunity. This study has highlighted in better understanding of the interorgan immunological communication network and identified potential metabolic ALARMINs. It will serve a broad readership in metabolic regulation of immunity and medical sciences.


The research work, entitled Sugar Alcohols of Polyol Pathway Serve as Alarmins to Mediate Local-Systemic Innate Immune Communication in Drosophila has published online in the journal Cell Host Microbe on July 23rd, 2019. Dr. Shuo Yang (IPS, CAS), Dr. Yaya Zhao (The Joint Center between Guangzhou Institute of Pediatrics and IPS, CAS) and Dr. Junjing Yu (SIBCB, CAS) are the co-first authors of this paper. Professor Lei Pan (IPS, CAS) and Professor Hong Tang (IPS, CAS) are co-correspondence authors. This work was supported by grants from Strategic Priority Research Program of CAS, National Natural Science Foundation of China and CAS Youth Innovation Promotion Association.