TREM-2 Drives Development of Multiple Sclerosis by Promoting Pathogenic Th17 Polarization
Siying Qu1 · Shengfeng Hu2 · Huiting Xu1 · Yongjian Wu1 · Siqi Ming1 · Xiaoxia Zhan3 · Cheng Wang4 · Xi Huang11 Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Afliated Hospital of Sun Yat-sen University, Zhuhai 519000, China
2 The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, The Second Afliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
3 Department of Laboratory Medicine, The First Afliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
4 Division of Nephrology, Department of Medicine, the Fifth Afliated Hospital of Sun Yat-sen University, Zhuhai 519000, China
Abstract
Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease, mediated by pathogenic T helper 17 (Th17) cells. However, the therapeutic effect is accompanied by the fluctuation of the proportion and function of Th17 cells, which prompted us to find the key regulator of Th17 differentiation in MS. Here, we demonstrated that the triggering receptor expressed on myeloid cells 2 (TREM-2), a modulator of pattern recognition receptors on innate immune cells, was highly expressed on pathogenic CD4-positive T lymphocyte (CD4+ T) cells in both patients with MS and experimental autoimmune encephalomyelitis (EAE) mouse models. Conditional knockout of Trem-2 in CD4+ T cells significantly alleviated the disease activity and reduced Th17 cell infiltration, activation, differentiation, and inflammatory cytokine production and secretion in EAE mice. Furthermore, with Trem-2 knockout in vivo experiments and in vitro inhibitor assays, the TREM-2/zeta-chain associated protein kinase 70 (ZAP70)/signal transducer and activator of transcription 3 (STAT3) signal axis was essential for Th17 activation and differentiation in EAE progression. In conclusion, TREM-2 is a key regulator of pathogenic Th17 in EAE mice, and this sheds new light on the potential of this therapeutic target for MS.
Keywords
Multiple sclerosis; Experimental autoimmune encephalomyelitis; T helper 17; Triggering receptor expressed on myeloid cells 2
