| Summary: | 碩士 === 國立陽明大學 === 微生物及免疫學研究所 === 104 === Chronic Kidney Disease (CKD) is highly prevalent in Taiwan. Along the disease progressed, many patients turn to end stage renal disease (ESRD) and have dysfunctional kidneys. Triggering Receptor Expressed on Myeloid cells (TREM) is an immunoglobulin-like receptor superfamily. Three murine TREM members, TREM-1, TREM-2 and TREM-3, has been identified in mouse. Among them, TREM-2 is uniquely noticed for its anti-inflammation function. Previously we found that TREM-2 can suppress Unilateral Ureteral Obstruction (UUO)-mediated kidney damage by down-regulating neutrophil infiltration in mice. An increase of renal infiltrated neutrophils which lead to severe kidney damage and fibrosis was observed in UUO-treated TREM-2 KO mice. Along the line, much more IL-17A (a potent pro-inflammatory cytokine that recruits neutrophils) transcription could be detected in the kidneys of TREM-2 KO mice. Theoretically, IL-17A is the key signature cytokine secreted by Th17 cells. TREM-2 expressing innate immune cells such as DCs or macrophages may play important roles as Antigen-Presenting Cells (APC), involve in Th17 cell’s maturation and activation. Upon antigen presentation, with the signals provided from APCs, naïve T cell could be differentiated into Th17 cells. TREM-2 expressing dendritic cells have the best capability of antigen presentation among all innate immune cells. Thus, we anticipate that TREM-2 regulates IL-17A-producing Th17 cell via modulating the function of dendritic cells.
In this study, we co-cultured dendritic cells with naïve T cells and collect mRNA and supernatant for further analyzes. After co-culture with TREM-2 KO dendritic cell, CD4+ T helper cells expressed higher IL-17A than those co-cultured with WT dendritic cell did. Three essential signals, MHC-TCR complex, co-stimulator and cytokines, have to be activated to trigger naïve T cells into mature effector cells. Cytokines are the key factors which decide the differentiation fate of T helper cells. However, further examination on Th17-differentiating cytokines, such as IL-23, IL-6 and TGF-β, revealed that there is no significant difference between WT and TREM-2 KO dendritic cell on secreting these cytokines. RORγt, the characteristic transcription factor of Th17, has been found could be functional inhibited by nitration. Our preliminary data shows that TREM-2 can mediate iNOS production, which are critical enzymes to mediate NO generation in myeloid cells, suggested that Th17 differentiation could be down-regulated by TREM-2-mediated iNOS-NO in dendritic cell upon antigen presentation. So we examine Th17 nitration signal in T helper cells and found the signal is down-regulated in the ones co-cultured with TREM-2 KO dendritic cells. Taken together, our results revealed a TREM-2-iNOS-NO regulation on Th17 differentiation upon DC-T helper cells interaction which may involves in UUO nephritis.
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