Pharmacological targeting cGAS/STING/NF-κB axis by tryptanthrin induces microglia polarization toward M2 phenotype and promotes functional recovery in a mouse model of spinal cord injury

The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury.Regulation of shifting microglia polarization from M1(neurotoxic and proinflammatory type)to M2(neuroprotective and anti-inflammatory type)after spinal cord injury appears to be crucial.Tryptanthrin possesses an anti-inflammatory biological function.However,its roles and the underlying molecular mechanisms in spinal cord injury remain unknown.In this study,we found that tryptanthrin inhibited microglia-derived inflammation by promoting polarization to the M2 phenotype in vitro.Tryptanthrin promoted M2 polarization through inactivating the cGAS/STING/NF-κB pathway.Additionally,we found that targeting the cGAS/STING/NF-κB pathway with tryptanthrin shifted microglia from the M1 to M2 phenotype after spinal cord injury,inhibited neuronal loss,and promoted tissue repair and functional recovery in a mouse model of spinal cord injury.Finally,using a conditional co-culture system,we found that microglia treated with tryptanthrin suppressed endoplasmic reticulum stress-related neuronal apoptosis.Taken together,these results suggest that by targeting the cGAS/STING/NF-κB axis,tryptanthrin attenuates microglia-derived neuroinflammation and promotes functional recovery after spinal cord injury through shifting microglia polarization to the M2 phenotype.

Microglia Share the Burden

Parkinson's disease(PD),diffuse Lewy body disease(DLBD),and multiple system atrophy(MSA)are major neurodegenerative disorders;they are synucleinopathies,whose pathogenesis is due to the aggregation ofα-synuclein(α-syn)[1].α-syn is a 140 amino acid presynaptic protein that is composed of three domains:the N-terminal region[amino-acids(AA)1-60];the central domain with a non-Aβcomponent(AA 61-95),and the C-terminal acidic carboxyl-terminal tail(AA 96-140)[2].The structure of the protein exhibits different forms such as monomers,oligomers,fibrils,or fibers,which largely depend on the intracellular environment.Under pathological circumstances,monomericα-syn tends to form amyloid fibrils which finally condense into Lewy bodies[3].

Sodium-Calcium Exchanger-3 Plays Critical Roles in Pain"Wind-up"

Chronic pain,broadly described as pain lasting longer than 3 months,is a classic example of gene-environment interaction[1].A couple of types of chronic pain have also been shown to have complex heritable properties with a polygenic component[2].Quantitative Sensory Testing(QST)is a formal variant of the sensory examination,including"static"sensory profiling and"dynamic"QST.QST contributes to the prediction of vulnerable subpopulations and effective mechanisms.In addition,a deficit in dynamic QST has been proposed as a predictor of chronic pain[3].

An Empathic Pain-Regulated Neural Circuit

Empathy is a general term in psychology that refers to the correct understanding of the feelings and emotions of others,so as to achieve mutual understanding,care,and harmony.Empathic behavior is common in rodents[1],and various emotions such as pain,happiness and fear can be transmitted in the form of empathy.