Extracellular cold-inducible RNA-binding protein (eCIRP) plays a vital role in the inflammatory response during cerebral ischaemia. However, the potential role and regulatory mechanism of eCIRP in traumatic brain injury (TBI) remain unclear. Here, we explored the effect of eCIRP on the development of TBI using a neural-specific CIRP knockout (KO) mouse model to determine the contribution of eCIRP to TBI-induced neuronal injury and to discover novel therapeutic targets for TBI.

TBI animal models were generated in mice using the fluid percussion injury method. Microglia or neuron lines were subjected to different drug interventions. Histological and functional changes were observed by immunofluorescence and neurobehavioural testing. Apoptosis was examined by a TdT-mediated dUTP nick end labelling assay in vivo or by an annexin-V assay in vitro. Ultrastructural alterations in the cells were examined via electron microscopy. Tissue acetylation alterations were identified by non-labelled quantitative acetylation via proteomics. Protein or mRNA expression in cells and tissues was determined by western blot analysis or real-time quantitative polymerase chain reaction. The levels of inflammatory cytokines and mediators in the serum and supernatants were measured via enzyme-linked immunoassay.

There were closely positive correlations between eCIRP and inflammatory mediators, and between eCIRP and TBI markers in human and mouse serum. Neural-specific eCIRP KO decreased hemispheric volume loss and neuronal apoptosis and alleviated glial cell activation and neurological function damage after TBI. In contrast, eCIRP treatment resulted in endoplasmic reticulum disruption and ER stress (ERS)-related death of neurons and enhanced inflammatory mediators by glial cells. Mechanistically, we noted that eCIRP-induced neural apoptosis was associated with the activation of the protein kinase RNA-like ER kinase-activating transcription factor 4 (ATF4)-C/EBP homologous protein signalling pathway, and that eCIRP-induced microglial inflammation was associated with histone H3 acetylation and the α7 nicotinic acetylcholine receptor.

These results suggest that TBI obviously enhances the secretion of eCIRP, thereby resulting in neural damage and inflammation in TBI. eCIRP may be a biomarker of TBI that can mediate the apoptosis of neuronal cells through the ERS apoptotic pathway and regulate the inflammatory response of microglia via histone modification.

Sepsis is a life-threatening condition characterized by profound immune dysregulation and organ dysfunction. The functional impairment of dendritic cells (DCs) in septic patients is well-documented and contributes significantly to sepsis-induced immunosuppression; yet the underlying mechanisms remain poorly understood. Tripartite motif 13 (TRIM13) has been identified as an immune regulator with predominantly suppressive effects. Here, we aimed to investigate the potential role of TRIM13 restriction in promoting the DC-mediated immune response during sepsis.

Splenic DCs were isolated from wild-type (WT) and DC-specific Trim13 conditional knockout (Trim13 cKO) mice post-cecum ligation and puncture (CLP). These cells were subsequently analyzed by proteomics, immunoblotting, flow cytometry, and transmission electron microscopy (TEM). DC2.4 cells were infected with either Trim13 shRNA or a Trim13 overexpression lentiviral vector and treated with different pharmacological inhibitors. Protein interactions were examined via coimmunoprecipitation (Co-IP) and confocal microscopy. Cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA), and organ lesions were assessed through hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC) for CD45, and TUNEL assays.

TRIM13 expression was rapidly upregulated in DCs following septic challenge. Deletion of TRIM13 in DCs disrupted the endoplasmic reticulum (ER)-associated degradation (ERAD) and ER-selective autophagy (ER-phagy)-mediated degradation of the stimulator of interferon genes (STING), leading to sustained STING activation and enhanced DC function. STING signaling promoted the p-IRF3 nuclear translocation, NLRP3 inflammasome priming, and transient DC pyroptosis, thereby exacerbating hyperinflammation in the acute phase of sepsis. Over the longer term, prolonged STING signaling inhibited DCs from adopting the immunosuppressive phenotype and promoting the DC-mediated immune response. Ultimately, TRIM13 deficiency in DCs ameliorated sepsis-induced immunosuppression, preserved organ function in the late phase of sepsis, and reduced overall mortality in septic mice.

TRIM13 acts as a key negative regulator of DC function during sepsis. Restricting TRIM13 sustains DC immunostimulatory property, counteracts sepsis-induced immunosuppression, and improves survival outcomes. These findings highlight TRIM13 as a potential therapeutic target for sepsis management.

Dendritic cells are crucial in the development of sepsis, yet the effect of ribophagy on dendritic cell activation remains unclear. This study aimed to investigate the potential role of nuclear fragile X mental retardation-interacting protein 1 (NUFIP1), a selective autophagy receptor, on sequestering ribosomes in autophagosomes to maintain dendritic cell function during early stages of sepsis.

Splenic dendritic cells were isolated using CD11c⁺ microbeads and treated with lipopolysaccharide. Sepsis models were generated using cecal ligation and puncture. Expression of dendritic cell surface molecules was detected using flow cytometry. Cytokine level was quantified using enzyme-linked immunosorbent assay kits. Laser scanning confocal microscopy was employed to observe ribophagy and endoplasmic reticulum (ER) morphology. Transmission electron microscopy was used to examine autophagosomes containing ribosomes. Western blotting was performed to determine the levels of ribophagy- and ER stress-associated proteins.

The results showed that NUFIP1-mediated ribophagy was significantly activated under septic challenge and facilitated the functional activation of dendritic cells by mitigating excessive ER stress. Deletion of Nufip1 resulted in reduced expression of surface molecules on dendritic cells, inhibited T-cell proliferation, exacerbated peripheral immunosuppression and severe multiple organ damage, and increased mortality. Salubrinal, a specific inhibitor of EIF2A dephosphorylation, rescued dendritic cell dysfunction in septic mice with Nufip1 deficiency. Mechanistically, NUFIP1 interacted directly with ATF4 and regulated its nuclear translocation.

These findings suggest that NUFIP1 regulates ER stress through the EIF2AK3–ATF4–damage-inducible transcript 3 pathway, highlighting its critical regulatory role in sepsis. Thus, NUFIP1 represents a new target for sepsis therapy.