Neuronally-expressed Sarm1 regulates expression of inflammatory and antiviral cytokines in brains.

Sarm1 is the fifth Toll/IL-1 receptor (TIR) domain-containing adaptor protein identified to regulate TLR downstream signaling. Unlike the other TIR domain-containing adaptor proteins, Sarm1 is predominantly expressed in the brain. Our previous study indicated that Sarm1 regulates dendritic growth, axonal extension and neuronal polarity. Here, we investigated whether Sarm1 is involved in innate immunity in the brain. First, regional and cell-type distribution of Sarm1 in mouse brains was revealed using double immunostaining. Sarm1 was widely distributed in different regions of brains, including the cerebral cortex, hippocampus, amygdala, cerebellum and midbrain. Moreover, Sarm1 is present in both projection and inhibitory neurons, but, interestingly, not in microglial cells--the main immune cells in the brain. These results suggest that Sarm1 is unlikely to regulate microglial activity in a cell-autonomous manner. However, compared with wild type littermates, the RNA expression levels of several inflammatory and antiviral cytokines were altered in the embryonic and adult brains of Sarm1 knockdown transgenic mice. These data imply that Sarm1 influences cytokine expression in neurons. In conclusion, our findings suggest that Sarm1 regulates the innate immune responses of the central nervous system through regulating the inflammatory and anti-virus cytokines produced by neurons.