An anti-inflammatory transcriptional cascade conserved from flies to humans

Innate immunity is an ancestral process that can induce pro- and anti-inflammatory states. A major challenge is to characterize transcriptional cascades that modulate the response to inflammation. Since the Drosophila glial cells missing (Gcm) transcription factor has an anti-inflammatory role, we explored its regulation and evolutionary conservation. Here, we show that the murine Gcm2 (mGcm2) gene is expressed in a subpopulation of aged microglia (chronic inflammation) and upon lysophosphatidylcholine (LPC)-induced central nervous system (CNS) demyelination (acute inflammation). Moreover, mGcm2 conditional knockout mice show an increased inflammatory phenotype upon aging or LPC injection, and hGCM2 is expressed in active demyelinating lesions of patients with multiple sclerosis. Finally, Drosophila Gcm expression is induced upon aging and acute challenge, and its overexpression decreases the inflammatory phenotype. Altogether, these data indicate that the inducible Gcm cascade is conserved from flies to humans and represents a potential therapeutic target in the control of the inflammatory response. [Display omitted] •mGcm2 is expressed in murine microglia during chronic and acute inflammatory responses•mGcm2 conditional knockout mice show an increased pro-inflammatory profile•hGCM2 is expressed in microglia of patients with multiple sclerosis•Gcm expression in hemocytes negatively controls the inflammatory state Pavlidaki et al. show that the Gcm cascade has an evolutionary conserved role from flies to mice and humans. Deletion of Gcm leads to increased pro-inflammatory responses during acute and chronic inflammation in both mice and flies. Finally, GCM2 is present in acute inflammatory conditions in brain lesions in humans.