TIA1-mediated stress granules inhibit the neuroinflammation and neurodegeneration after spinal cord injury through LCN2 signaling

Spinal cord injury (SCI), a complex and serious neurological disease may induce severe cellular stress. In response to stress signals, cells form stress granules (SGs) as protective measures, and T-cell intracellular antigen 1 (TIA1) is a vital component of SGs. However, the roles and mechanism of TIA1-mediated SGs in SCI remain unknown. In this study, we found that TIA1 was upregulated in the cytoplasm of neurons and co-localized with the cytoplasmic G3BP1+ SGs. Furthermore, Tia1 knockout in the CNS (Tia1Nestin-CKO mice) did not affect the development of the spinal cords and locomotion function, but impeded the neural regeneration, and then inhibited the functional recovery after SCI, whereas, Tia1 knockout in the astrocytes (Tia1GFAP-CKO mice) did not affect development of the spinal cords and the locomotion functional recovery after SCI. Mechanistically, we found that Tia1 deletion decreased the formation of SGs, and increased the lipocalin 2 (LCN2, a secreted protein) expression in neurons through decreasing the sequestration of their mRNA into SGs after SCI, which further induced the neuroinflammation by activating astrocytes and microglia through cGAS-STING signaling pathway. Finally, treatment with deferoxamine (DFO), an inhibitor of LCN2, inhibited the neuroinflammation and partially restored the deficits in neural degeneration and functional recovery after SCI in Tia1Nestin-CKO mice. Together, these results suggest neuronal TIA1-mediated SGs encapsulates lcn2 mRNA, halting its translation and thereby attenuating the neuroinflammation and promoted the functional recovery after SCI, and TIA1-mediated SGs serves as a novel strategy for SCI treatment by regulating neuroinflammation.