STING deficiency promotes motor recovery in mice following brachial plexus root avulsion

Abstract

Background: Brachial plexus root avulsion (BPRA), a well-known form of peripheral nerve injury, results in motor function loss in the affected forelimb due to motoneuron (MN) death, which may be influenced by neuroinflammation following a lesion in the spinal cord. Although synthase-stimulator of interferon genes (STING) signaling can contribute to chronic inflammation and tissue damage in a number of pathological conditions, the essential role of STING signaling in BPRA remains to be reported. Based on our previous findings that the STING mRNA level is upregulated in the anterior horn of the segment of the affected spinal cords of mice with BPRA, STING may be associated with motor recovery in BPRA.

Methods: In the present study, STING knockout transgenic mice were used to establish a BPRA re-implantation model, which was followed by behavioral tests, histochemical staining and quantitative reverse transcription polymerase chain reaction.

Results: The results demonstrated that STING deficiency can increase the body weight, promote motor recovery, decrease MN death, inhibit pyroptosis and neuroinflammation, increase remyelination, and reduce the atrophy of the biceps brachii in mice with BPRA.

Conclusion: These combined results suggest that inhibition of STING may be a promising strategy for treating BPRA.

Keywords

brachial plexus root avulsion (BPRA) / motoneuron (MN) / neuroinflammation / synthase-stimulator of interferon genes (STING)

References

[1] Kaiser R, Waldauf P, Ullas G, Krajcová A. Epidemiology, etiology, and types of severe adult brachial plexus injuries requiring surgical repair: systematic review and meta-analysis. Neurosurg Rev. 2020; 43(2): 443-452.

[2] Ruven C, Badea SR, Wong WM, Wu W. Combination treatment with exogenous GDNF and fetal spinal cord cells results in better motoneuron survival and functional recovery after avulsion injury with delayed root reimplantation. J Neuropathol Exp Neurol. 2018; 77(4): 325-343.

[3] Haninec P, Šámal F, Tomáš R, Houstava L, Dubový P. Direct repair (nerve grafting), neurotization, and end-to-side neurorrhaphy in the treatment of brachial plexus injury. J Neurosurg. 2007; 106(3): 391-399.

[4] Rodrigues-Filho R, Santos ARS, Bertelli JA, Calixto JB. Avulsion injury of the rat brachial plexus triggers hyperalgesia and allodynia in the hindpaws: a new model for the study of neuropathic pain. Brain Res. 2003; 982(2): 186-194.

[5] Carlstedt T, Anand P, Htut M, Misra P, Svensson M. Restoration of hand function and so called “breathing arm” after intraspinal repair of C5-T1 brachial plexus avulsion injury. Case report. Neurosurg Focus. 2004; 16(5):E7.

[6] Carlstedt T. Root repair review: basic science background and clinical outcome. Restor Neurol Neurosci. 2008; 26(2–3): 225-241.

[7] McKay Hart A, Brannstrom T, Wiberg M, Terenghi G. Primary sensory neurons and satellite cells after peripheral axotomy in the adult rat: timecourse of cell death and elimination. Exp Brain Res. 2002; 142(3): 308-318.

[8] Huang Y, Mai Y, Ye W, et al. Brachial plexus root avulsion injury-induced endothelin-converting enzyme-like 1 overexpression is associated with injured motor neurons survival. Mol Neurobiol. 2024; 61(8): 5194-5205.

[9] Su M, Guan H, Zhang F, Gao Y, Teng X, Yang W. HDAC6 regulates the chaperone-mediated autophagy to prevent oxidative damage in injured neurons after experimental spinal cord injury. Oxidative Med Cell Longev. 2016; 2016:7263736.

[10] Zhong K, Huang Y, Zilundu PM, et al. Motor neuron survival is associated with reduced neuroinflammation and increased autophagy after brachial plexus avulsion injury in aldose reductase-deficient mice. J Neuroinflammation. 2022; 19(1): 271.

[11] Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008; 455(7213): 674-678.

[12] Li T, Chen ZJ. The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. J Exp Med. 2018; 215(5): 1287-1299.

[13] Skopelja-Gardner S, An J, Elkon KB. Role of the cGAS-STING pathway in systemic and organ-specific diseases. Nat Rev Nephrol. 2022; 18(9): 558-572.

[14] Zhao J, Xiao R, Zeng R, He E, Zhang A. Small molecules targeting cGAS-STING pathway for autoimmune disease. Eur J Med Chem. 2022; 238:114480.

[15] Quek H, Luff J, Cheung K, et al. A rat model of ataxia-telangiectasia: evidence for a neurodegenerative phenotype. Hum Mol Genet. 2017; 26(1): 109-123.

[16] Nazmi A, Field RH, Griffin EW, et al. Chronic neurodegeneration induces type I interferon synthesis via STING, shaping microglial phenotype and accelerating disease progression. Glia. 2019; 67(7): 1254-1276.

[17] Huang R, Shi Q, Zhang S, et al. Inhibition of the cGAS-STING pathway attenuates lung ischemia/reperfusion injury via regulating endoplasmic reticulum stress in alveolar epithelial type II cells of rats. J Inflamm Res. 2022; 15: 5103-5119.

[18] Chen S, Hou Y, Zhao Z, et al. Neuregulin-1 accelerates functional motor recovery by improving motoneuron survival after brachial plexus root avulsion in mice. Neuroscience. 2019; 404: 510-518.

[19] Li S, He B, Zhou G, et al. Curcumin promotes the recovery of motor function after brachial plexus avulsion injury in rats. Brain Behav. 2025; 15(8):e70728.

[20] Li S, Wu L, Xie J, et al. Edaravone improves motor dysfunction following brachial plexus avulsion injury in rats. ACS Chem Neurosci. 2025; 16(3): 479-489.

[21] Bertelli JA, Mira JC. Behavioral evaluating methods in the objective clinical assessment of motor function after experimental brachial plexus reconstruction in the rat. J Neurosci Methods. 1993; 46(3): 203-208.

[22] Chen S, Wu L, He B, et al. Artemisinin facilitates motor function recovery by enhancing motoneuronal survival and axonal Remyelination in rats following brachial plexus root avulsion. ACS Chem Neurosci. 2021; 12(17): 3148-3156.

[23] Wu L, Chen S, He B, et al. Acetylglutamine facilitates motor recovery and alleviates neuropathic pain after brachial plexus root avulsion in rats. J Transl Med. 2023; 21(1): 563.

[24] He L, Liu D, Zhou W, et al. The innate immune sensor STING accelerates neointima formation via NF-kappaB signaling pathway. Int Immunopharmacol. 2023; 121:110412.

[25] Tan J, Yi S, Xiao Z, et al. Mitochonic acid 5 promotes the migration of mouse microglial BV-2 cells in the presence of LPS-induced inflammation via Mfn2-associated mitophagy. Acta Neurobiol Exp (Wars). 2022; 82(4): 442-447.

[26] Shin AY, Spinner RJ, Steinmann SP, Bishop AT. Adult traumatic brachial plexus injuries. J Am Acad Orthop Surg. 2005; 13(6): 382-396.

[27] Kachramanoglou C, Carlstedt T, Koltzenburg M, Choi D. Long-term outcome of brachial plexus reimplantation after complete brachial plexus avulsion injury. World Neurosurg. 2017; 103: 28-36.

[28] Zhao RR, Andrews MR, Wang D, et al. Combination treatment with anti-Nogo-A and chondroitinase ABC is more effective than single treatments at enhancing functional recovery after spinal cord injury. Eur J Neurosci. 2013; 38(6): 2946-2961.

[29] Chen S, He B, Zhou G, et al. Berberine enhances L1 expression and axonal remyelination in rats after brachial plexus root avulsion. Brain Behav. 2020; 10(10):e01792.

[30] Eggers R, Tannemaat MR, Ehlert EM, Verhaagen J. A spatio-temporal analysis of motoneuron survival, axonal regeneration and neurotrophic factor expression after lumbar ventral root avulsion and implantation. Exp Neurol. 2010; 223(1): 207-220.

[31] Wu W, Li L. Inhibition of nitric oxide synthase reduces motoneuron death due to spinal root avulsion. Neurosci Lett. 1993; 153(2): 121-124.

[32] Tang Y, Ling ZM, Fu R, et al. Time-specific microRNA changes during spinal motoneuron degeneration in adult rats following unilateral brachial plexus root avulsion: ipsilateral vs. contralateral changes. BMC Neurosci. 2014; 15: 92.

[33] Barbizan R, Oliveira AL. Impact of acute inflammation on spinal motoneuron synaptic plasticity following ventral root avulsion. J Neuroinflammation. 2010; 7: 29.

[34] Yuan Q, Xie Y, So KF, Wu W. Inflammatory response associated with axonal injury to spinal motoneurons in newborn rats. Dev Neurosci. 2003; 25(1): 72-78.

[35] Ohlsson M, Hoang TX, Wu J, Havton LA. Glial reactions in a rodent cauda equina injury and repair model. Exp Brain Res. 2006; 170(1): 52-60.

[36] Wang W, Hu D, Wu C, et al. STING promotes NLRP3 localization in ER and facilitates NLRP3 deubiquitination to activate the inflammasome upon HSV-1 infection. PLoS Pathog. 2020; 16(3):e1008335.

[37] Gaidt MM, Ebert TS, Chauhan D, et al. The DNA inflammasome in human myeloid cells is initiated by a STING-cell death program upstream of NLRP3. Cell. 2017; 171(5): 1110-1124.e18.

[38] Fang XY, Zhang WM, Zhang CF, et al. Lithium accelerates functional motor recovery by improving remyelination of regenerating axons following ventral root avulsion and reimplantation. Neuroscience. 2016; 329: 213-225.

[39] Duijnisveld BJ, Henseler JF, Reijnierse M, Fiocco M, Kan HE, Nelissen RGHH. Quantitative Dixon MRI sequences to relate muscle atrophy and fatty degeneration with range of motion and muscle force in brachial plexus injury. Magn Reson Imaging. 2017; 36: 98-104.

[40] Kugelberg E, Edström L, Abbruzzese M. Mapping of motor units in experimentally reinnervated rat muscle. Interpretation of histochemical and atrophic fibre patterns in neurogenic lesions. J Neurol Neurosurg Psychiatry. 1970; 33(3): 319-329.

[41] Connor EA, McMahan UJ. Cell accumulation in the junctional region of denervated muscle. J Cell Biol. 1987; 104(1): 109-120.

RIGHTS & PERMISSIONS

2025 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.