A Novel snoRNA, Gm24418 Attenuates Inflammation Injury After Acute TBI Through Regulating CCL2

Traumatic brain injury (TBI) triggers profound neuroinflammatory responses; however, the regulatory role of small nucleolar RNAs (snoRNAs) in TBI-associated neuroinflammation remains poorly understood. This study evaluated its prognostic value in TBI.

A controlled cortical impact (CCI) model was established in male C57BL/6 mice and validated through modified neurological severity scoring (mNSS), hematoxylin-eosin (H&E) staining, and immunostaining for IgG leakage and Nissl substance. Cortical snoRNA expression profiles were assessed using microarray analysis, with differentially expressed candidates confirmed by quantitative real-time PCR (qRT-PCR). The spatial distribution of snoRNAs was determined via fluorescence in situ hybridization (FISH), while the anti-inflammatory effects of snoRNA Gm24418 were evaluated in vivo and vitro. Downstream molecular pathways were identified through transcriptomic sequencing combined with bioinformatics analysis.

Mice subjected to CCI exhibited significant motor and cognitive impairments (elevated mNSS), neuronal loss (as indicated by H&E and Nissl staining), and blood-brain barrier disruption (evidenced by IgG extravasation). Microarray analysis identified 47 dysregulated small nucleolar RNAs (snoRNAs), comprising 43 that were downregulated and 4 that were upregulated, with Gm24418 exhibiting the most significant downregulation. FISH confirmed the localization of Gm24418 predominantly in cortical neurons. Overexpression of Gm24418 in N₂A cells and mice significantly reduced the levels of pro-inflammatory cytokines, including IL-1β, TNF-α, and IL-6, and suppressed the activation of Ccl2 and TNF signaling pathways. Mechanistic analyses indicated that Gm24418 overexpression is associated with downregulation of the TNF signaling pathway, thereby attenuating neuroinflammation and promoting the restoration of blood-brain barrier integrity following TBI.

Gm24418 is identified as a neuron-specific snoRNA that ameliorates TBI-induced neuropathology through influencing the expression of key inflammatory mediators, including CCL2 and TNF-α, representing a promising novel therapeutic target for post-traumatic neuroinflammation.