Urolithin A is a potent modulator of cGAS-Sting signaling pathway

The innate immune cGAS-STING pathway has emerged as an important signaling system in the organismal defense against viral and bacterial infections, inflammatory responses to cellular damage, regulation of autophagy, as well as in tumor immunosurveillance. Such key functions of the cGAS-STING pathway make it an attractive target for pharmacological intervention in disease treatments and in controlling inflammation and immunity. Here, we show that urolithin A (UA), an ellagic acid metabolite, exerts a profound effect on the expression of STING and enhances cGAS-STING activation and STING-related autophagy in response to cytosolic DNA in human cell lines. Animal laboratory models and limited human trials have reported no obvious adverse effects of UA administration. Thus, the use of UA alone or in combination with other pharmacological compounds may present a potential therapeutic approach in the treatment of human diseases that involves aberrant activation of the cGAS-STING pathway or accumulation of cytosolic DNA and warrants further investigation in relevant transgenic animal models. HMC3 immortalized human microglial cells were incubated in growth medium containing either no (Control, N=3), or Urolithin A(UA, 10 μM for five days and 12.5 μM UA for 48 hours, N=3), while 500 ng double-stranded DNA (DNA) was added to cells with or without prior UA stimulation (UA+DNA and DNA, respectively, N=3 for each experiment). The NanoString human neuroinflammation panel (XT-CSO-MNROI1-12) with nCounter read-out was used to assay gene expression changes.