| Summary: | 博士 === 國立陽明大學 === 微生物及免疫學研究所 === 102 === Innate immunity is critical for host defense against pathogens, however, excessive inflammation may also cause serious tissue damages. Therefore, fine-tuning of the inflammation is important in the homeostasis of host innate immunity. Triggering receptors expressed on myeloid cells (TREM) have been found involved in modulating the innate immunity either by amplifying or dampening inflammatory responses. TREM family members have been found critical in various infectious or non-infectious diseases, but the details of the involved mechanisms remain largely unknown. In the present study, we investigated the inflammatory regulating mechanisms mediated by TREM-1 and TREM-2 by using two aseptic inflammatory disease models respectively. TREM-1 has been reported involved in pro-inflammatory responses. In the first part of this thesis, we determined the role of TREM-1 in chronic kidney disease (CKD) by adopting an experimental unilateral ureteral obstruction nephritis mouse model in TREM-1 deficient mice. TREM-1 is crucial for modulating M1 macrophage polarization, and has a pivotal role in mediating tubular injury and interstitial collagen deposition in obstructive nephritis. Lysates from nephritic wild type kidneys triggered a TREM-1-dependent M1 polarization ex vivo, consistent with the observation that granulocyte macrophage colony-stimulating factor (GM-CSF)-derived M1 macrophages express higher levels of TREM-1 in comparison with M-CSF-derived cells. Moreover, agonistic TREM-1 crosslink significantly strengthens the inductions of iNOS and GMCSF in M1 cells. These observations are validated by a strong clinical correlation between infiltrating TREM-1-expressing/iNOS-positive macrophages and renal injury in human obstructive nephropathy. Thus, TREM-1 may be a potential diagnostic and therapeutic target in human kidney disease. By contrast, TREM-2 is a phagocytic receptor involves in bacteria uptake and apoptotic cell clearance. Gout is an inflammatory joint disease caused by joint monosodium urate (MSU) crystals deposition which activates macrophage, mediates crystal phagocytosis, and further leads to NLRP3 inflammasome activation and IL-1β secretion. However, whether TREM-2 plays role in MSU crystals-mediated macrophage activation remains to be investigated. In the second part of this study, we found that serum soluble TREM-2 (sTREM-2) level is much higher in gout patients than in healthy donors. Our in vitro data also revealed that TREM-2 could interact with MSU crystals via extracellular domain (ECD), and play crucial role in mediating the inflammasome activation. Moreover, the uptake of MSU crystals was significantly reduced in macrophages lacking TREM-2. Correspondingly, a lower phosphorylation level of Src, a phagocytosis-related kinase, was observed in TREM-2 deficient macrophages. TREM-2 may mediate the MSU crystal recognition and play a crucial role in mediating downstream inflammasome activation. Taken all, we revealed novel regulatory mechanisms mediated by TREM-1 and TREM-2 in aseptic inflammatory diseases. These findings may provide new directions for developing new diagnostic and therapeutic strategies on inflammatory diseases.
|
|---|
