Neuroinflammation after traumatic brain injury (TBI) is enhanced in activating transcription factor 3 (ATF3) mutant mice

Traumatic brain injury (TBI) induces a neuroinflammatory response resulting in astrocyte and microglia activation at the lesion site. This involves up-regulation of neuroinflammatory genes including chemokines and interleukins. However, so far there is lack of knowledge on transcription factors (TFs) modulating this TBI associated gene expression response. Herein we analyzed activating transcription factor 3 (ATF3), a TF encoding a regeneration-associated gene (RAG) predominantly studied in peripheral nervous system (PNS) injury. ATF3 contributes to PNS axon regeneration and was shown before to regulate inflammatory processes in other injury models. In contrast to PNS injury, data on ATF3 in central nervous system (CNS) injury are sparse. We employed Atf3 mouse mutants and a closed-head weight-drop based TBI model in adult mice to target the rostro-lateral cortex resulting in moderate injury severity. After TBI, ATF3 was up-regulated already at early time-points (i.e. 1-4h) post injury in the brain. Mortality and weight loss upon TBI were slightly elevated in Atf3 mutants. ATF3 deficiency enhanced TBI induced paresis and hematoma formation suggesting that ATF3 limits these injury outcomes in wildtype mice. Next we analyzed TBI associated RAG and inflammatory gene expression in the cortical impact area. In contrast to the PNS, only some RAGs (Atf3, Timp1, Sprr1a) were induced by TBI and, surprisingly, some RAG encoding neuropeptides were down-regulated. Notably, we identified ATF3 as TF regulating pro-neuroinflammatory gene expression including CCL and CXCL chemokines (Ccl2, Ccl3, Ccl4 and Cxcl1) and lipocalin. In Atf3 mutant mice, mRNA abundance was further enhanced upon TBI compared to wildtype mice suggesting immune gene repression by wildtype ATF3. In accordance, more immune cells were present in the lesion area of ATF3 deficient mice. Overall, we identified ATF3 as a new TF mediating TBI associated CNS inflammatory responses.