Investigation On Immune Regulation Mechanism Of MALT1 Paracaspase Activity In Spinal Cord Injury

Spinal cord injury(SCI)is a devastating traumatic injury that causes persistent,severe motor and sensory dysfunction.After spinal cord injury,the blood-spinal cord barrier is destroyed and a large number of immune cells infiltrate into the injured site,causing an inflammatory response.Mucosa-associated lymphoid tissue lymphoma translocation 1(MALT1)has been shown to regulate the survival and differentiation of immune cells and plays a critical role in many diseases,but its function in lesion recovery after SCI remains unclear.In this paper,deficiency or inhibition of MALT1 paracaspase activity would promote functional recovery after SCI.First,in patients with SCI,PBMC showed increased MALT1 paracaspase activity.Second,we generated KI mice with a point mutation(C472G)in the active center of MALT1 and revealed that the KI mice exhibited improved functional recovery after SCI.Fewer macrophages were recruited to the injury site in KI mice and these macrophages were differentiated into M2 cells.Furthermore,to investigate the specific molecular mechanism by which MALT1 protease activity regulates spinal cord injury by regulating macrophages,we found that macrophages from the KI Mice exhibited reduced phosphorylation of p65,which in turn resulted in decreased SOCS3 expression and increased p STAT3 and p STAT6 levels.Inhibition of MALT1 paracaspase activity with the small molecule inhibitor “MI-2” or the more specific inhibitor “MLT-827” yielded similar results.Last but not least,human macrophages showed a reduced M1 phenotype and a stronger M2 phenotype following the inhibition of MALT1 paracaspase activity.These findings provided important clues suggesting that the inhibition of MALT1 paracaspase activity may improve lesion recovery in subjects with SCI in the clinic.