Genetic deletion of the apoptosis associated speck like protein containing a card in LysM+ macrophages attenuates spinal cord injury by regulating M1/M2 polarization through ASC-dependent inflammasome signaling axis

Shu-Qin Ding; Hua-Zheng Yan; Jian-Xiong Gao; Yu-Qing Chen; Nan Zhang; Rui Wang; Jiang-Yan Li; Jian-Guo Hu; He-Zuo Lü

doi:10.1016/j.expneurol.2024.114982

Genetic deletion of the apoptosis associated speck like protein containing a card in LysM⁺ macrophages attenuates spinal cord injury by regulating M1/M2 polarization through ASC-dependent inflammasome signaling axis

Exp Neurol. 2024 Sep 29:382:114982. doi: 10.1016/j.expneurol.2024.114982. Online ahead of print.

Authors

Shu-Qin Ding¹, Hua-Zheng Yan², Jian-Xiong Gao³, Yu-Qing Chen¹, Nan Zhang¹, Rui Wang⁴, Jiang-Yan Li¹, Jian-Guo Hu⁵, He-Zuo Lü⁶

Affiliations

¹ Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, PR China; Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, PR China.
² Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, PR China; Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, PR China; Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu, Anhui 233030, PR China.
³ Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, PR China; Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, PR China; Anhui Engineering Research Center for Neural Regeneration Technology and Medical New Materials, Bengbu Medical University, Bengbu, Anhui 233030, PR China.
⁴ Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, PR China.
⁵ Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, PR China; Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, Bengbu Medical University, Bengbu, Anhui 233030, PR China. Electronic address: jghu9200@163.com.
⁶ Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, PR China; Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, PR China; Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu, Anhui 233030, PR China; Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, Bengbu Medical University, Bengbu, Anhui 233030, PR China; Anhui Engineering Research Center for Neural Regeneration Technology and Medical New Materials, Bengbu Medical University, Bengbu, Anhui 233030, PR China. Electronic address: lhz233003@163.com.

PMID: 39353545
DOI: 10.1016/j.expneurol.2024.114982

Abstract

Apoptosis associated speck like protein containing a card (ASC), the key adaptor protein of the assembly and activation of canonical inflammasomes, has been found to play a significant role in neuroinflammation after spinal cord injury (SCI). The previous studies indicated that widely block or knockout ASC can ameliorate SCI. However, ASC is ubiquitously expressed in infiltrated macrophages and local microglia, so further exploration is needed on which type of cell playing the key role. In this study, using the LysM^cre;Asc^flox/flox mice with macrophage-specifc ASC conditional knockout (CKO) and contusive SCI model, we focus on evaluating the specific role of ASC in lysozyme 2 (LysM)⁺ myeloid cells (mainly infiltrated macrophages) in this pathology. The results revealed that macrophage-specifc Asc CKO exhibited the follow effects: (1) A significant reduction in the numbers of infiltrated macrophages in the all phases of SCI, and activated microglia in the acute and subacute phases. (2) A significant reduction in ASC, caspase-1, interleukin (IL)-1β, and IL-18 compared to control mice. (3) In the acute and subacute phases of SCI, M1 subset differentiation was inhibited, and M2 differentiation was increased. (4) Histology and hindlimb motor recoveries were improved. In conclusion, this study elucidates that macrophage-specific ASC CKO can improve nerve function recovery after SCI by regulating M1/M2 polarization through inhibiting ASC-dependent inflammasome signaling axis. This indicates that ASC in peripheral infiltrated macrophages may play an important role in SCI pathology, at least in mice, could be a potential target for treatment.

Keywords: Apoptosis-associated speck-like protein containing a card; Conditional gene knockout; LysM(+) macrophages; Spinal cord injury.