Inhibition of MALT1 paracaspase activity improves lesion recovery following spinal cord injury

Hua Zhang; Guodong Sun; Xiaowei Li; Zhen Fu; Chengbin Guo; Guangchao Cao; Baocheng Wang; Qian Wang; Shuxian Yang; Dehai Li; Xichun Xia; Peng Li; Jing Zhu; Wei Zhou; Liangyan Zheng; Jingxia Li; Lei Zhang; Jianlei Hao; Libing Zhou; Frederic Bornancin; Zhizhong Li; Zhinan Yin; Yunfei Gao

doi:10.1016/j.scib.2019.04.026

Inhibition of MALT1 paracaspase activity improves lesion recovery following spinal cord injury

Sci Bull (Beijing). 2019 Aug 30;64(16):1179-1194. doi: 10.1016/j.scib.2019.04.026. Epub 2019 Apr 22.

Authors

Hua Zhang¹, Guodong Sun², Xiaowei Li¹, Zhen Fu¹, Chengbin Guo¹, Guangchao Cao¹, Baocheng Wang¹, Qian Wang¹, Shuxian Yang¹, Dehai Li¹, Xichun Xia¹, Peng Li¹, Jing Zhu¹, Wei Zhou¹, Liangyan Zheng¹, Jingxia Li¹, Lei Zhang³, Jianlei Hao¹, Libing Zhou⁴, Frederic Bornancin⁵, Zhizhong Li⁶, Zhinan Yin⁷, Yunfei Gao⁸

Affiliations

¹ The First Affiliated Hospital, Biomedical Translational Research Institute and School of Pharmacy, Jinan University, Guangzhou 510632, China.
² Department of Orthopedics, First Affiliated Hospital, Jinan University, Guangzhou 510632, China.
³ Shandong Provincial Qianfoshan Hospital, Shandong First Medical University, Jinan 250014, China.
⁴ Guangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou 510632, China.
⁵ Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
⁶ Department of Orthopedics, Heyuan People's Hospital (Heyuan Affiliated Hospital of Jinan University), Heyuan 517199, China; Department of Orthopedics, First Affiliated Hospital, Jinan University, Guangzhou 510632, China. Electronic address: tzzli@jnu.edu.cn.
⁷ The First Affiliated Hospital, Biomedical Translational Research Institute and School of Pharmacy, Jinan University, Guangzhou 510632, China; State Key Laboratory of Biotherapy, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: zhinan.yin@yale.edu.
⁸ The First Affiliated Hospital, Biomedical Translational Research Institute and School of Pharmacy, Jinan University, Guangzhou 510632, China. Electronic address: tyunfeigao@jnu.edu.cn.

PMID: 36659689
DOI: 10.1016/j.scib.2019.04.026

Abstract

Spinal cord injury (SCI) is a devastating traumatic injury that causes persistent, severe motor and sensory dysfunction. Immune responses are involved in functional recovery after SCI. Mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) has been shown to regulate the survival and differentiation of immune cells and to play a critical role in many diseases, but its function in lesion recovery after SCI remains unclear. In this paper, we generated KI (knock in) mice with a point mutation (C472G) in the active center of MALT1 and found that the KI mice exhibited improved functional recovery after SCI. Fewer macrophages were recruited to the injury site in KI mice and these macrophages differentiated into anti-inflammatory macrophages. Moreover, macrophages from KI mice exhibited reduced phosphorylation of p65, which in turn resulted in decreased SOCS3 expression and increased pSTAT6 levels. Similar results were obtained upon inhibition of MALT1 paracaspase with the small molecule inhibitor "MI-2" or the more specific inhibitor "MLT-827". In patients with SCI, peripheral blood mononuclear cells (PBMC) displayed increased MALT1 paracaspase. Human macrophages showed reduced pro-inflammatory and increased anti-inflammatory characteristics following the inhibition of MALT1 paracaspase. These findings suggest that inhibition of MALT1 paracaspase activity in the clinic may improve lesion recovery in subjects with SCI.

Keywords: Anti-inflammatory macrophage; MALT1 paracaspase activity; NF-κB; Pro-inflammatory macrophage; Spinal cord injury.