| Summary: | 碩士 === 國立陽明大學 === 微生物及免疫學研究所 === 106 === Myeloid cells, including macrophages and dendritic cells, play as the first line of host defense like pathogen recognition, clearance and further induction of the adaptive immune responses. Macrophages can be classically activated by lipopolysaccharide (LPS)/interferon γ (IFNγ) and then produce cytokines and inducible nitric oxide synthase (iNOS) for promoting inflammation. Triggering Receptors Expressed on Myeloid cells-2 (TREM-2) is anti-inflammatory and can mediate diverse functions on different cell types. Previous study has reported that TREM-2 deficient macrophages produced more inflammatory cytokines upon TLR stimulation. The mitogen-activated protein kinases(MAPK) pathways, whose signal transduction could be induced by growth factors or extracellular stimuli like LPS, are essential for pro-inflammatory genes expression. Our previous data showed that the ERK activation level is higher in TREM-2 deficient microglia cells. In this study, we confirmed the ERK activation level is higher in LPS stimulated TREM-2 knock out bone marrow derived macrophages (BMDMs). Besides, we also found that the p38 is more activated in TREM-2 knock out BMDMs. Signal transducers and activators of transcription 1(STAT1) can be activated by IFNγ and MAPK and then promote pro-inflammatory cytokine production. We also examined the STAT1 activation level and found that the phosphorylation is higher in TREM-2 knock out BMDMs. These evidences can be referred as the reasons of why loss of TREM-2 could lead to more cytokine production.
Besides, mitogen-activated protein kinases phosphatase(MKP) family is a negative feedback of MAPK pathways. Among them, MKP-1 had been reported for its special functions on macrophages, such as regulating monocyte adhesion, migration and polarization. On the other hand, some references also showed that the nitrosylated MKP-1(SNO-MKP-1) has higher stability and activity. In our data, we found that the expression of MKP-1 was comparable with WT. However, the pMKP-1 level is sustained longer in TREM-2 knock out BMDMs. We also confirmed that the iNOS expression and NO production were lower in TREM-2 knock out BMDMs and TREM-2 deficient dendritic cell line. Further, we also discovered that the NO induced by LPS can modify MKP-1, and the SNO-MKP-1 level is lower in TREM-2 deficient cells. In this study, we found NO could regulate pro-inflammatory MAPK signals. Additionally, MKP-1 can be modified by NO induced from LPS which suggested that the level of SNO-MKP-1 may be a reason of the over-activation of MAPK in TREM-2-deficient macrophages.
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