Parashar Kaustubh, Schulte Fabian, Hardt Markus, Baker Olga J
School of Dentistry, The University of Utah, Salt Lake City, UT, USA.
Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, USA.
FASEB J. 2020 Jun;34(6):7733-7744. doi: 10.1096/fj.201902196R. Epub 2020 Apr 11.
Our previous results showed that the specialized pro-resolving mediator (SPM) Resolvin D1 (RvD1) promotes resolution of inflammation in salivary glands in non-obese diabetic (NOD)/ShiLtJ, a mouse model for Sjögren's syndrome (SS). Additionally, mice lacking the RvD1 receptor ALX/FPR2 show defective innate and adaptive immune responses in salivary glands. Particularly, ALX/FPR2 KO mice exhibit exacerbated inflammation in their salivary glands in response to systemic LPS treatment. Moreover, female ALX/FPR2 KO mice show increased autoantibody production and loss of salivary gland function with age. Together, these studies suggest that an underlying SPM dysregulation could be contributing to SS progression. Therefore, we investigated whether SPM production is altered in NOD/ShiLtJ using metabololipidomics and enzyme-linked immunosorbent assay (ELISA). Our results demonstrate that SPM levels were broadly elevated in plasma collected from NOD/ShiLtJ female mice after disease onset, whereas these drastic changes did not occur in male mice. Moreover, gene expression of enzymes involved in SPM biosynthesis were altered in submandibular glands (SMG) from NOD/ShiLtJ female mice after disease onset, with 5-LOX and 12/15-LOX being downregulated and upregulated, respectively. Despite this dysregulation, the abundances of the SPM products of these enzymes (ie, RvD1 and RvD2) were unaltered in freshly isolated SMG cells suggesting that other cell populations (eg, lymphocytes) may be responsible for the overabundance of SPMs that we observed. The elevation of SPMs noted here appeared to be sex mediated, meaning that it was observed only in one sex (females). Given that SS primarily affects females (roughly 90% of diagnosed cases), these results may provide some insights into the mechanisms underlying the observed sexual dimorphism.
我们之前的研究结果表明，特异性促消退介质（SPM）消退素D1（RvD1）可促进非肥胖糖尿病（NOD）/ShiLtJ小鼠唾液腺炎症的消退，NOD/ShiLtJ是干燥综合征（SS）的小鼠模型。此外，缺乏RvD1受体ALX/FPR2的小鼠在唾液腺中表现出先天性和适应性免疫反应缺陷。特别是，ALX/FPR2基因敲除（KO）小鼠在全身LPS处理后，唾液腺炎症加剧。此外，雌性ALX/FPR2 KO小鼠随着年龄增长，自身抗体产生增加，唾液腺功能丧失。总之，这些研究表明，潜在的SPM失调可能导致SS进展。因此，我们使用代谢脂质组学和酶联免疫吸附测定（ELISA）研究了NOD/ShiLtJ小鼠中SPM的产生是否发生改变。我们的结果表明，疾病发作后从NOD/ShiLtJ雌性小鼠采集的血浆中SPM水平普遍升高，而雄性小鼠未出现这些显著变化。此外，疾病发作后，NOD/ShiLtJ雌性小鼠下颌下腺（SMG）中参与SPM生物合成的酶的基因表达发生改变，5-脂氧合酶（5-LOX）和12/15-脂氧合酶分别下调和上调。尽管存在这种失调，但在新鲜分离的SMG细胞中，这些酶的SPM产物（即RvD1和RvD2）的丰度未发生改变，这表明其他细胞群体（如淋巴细胞）可能是我们观察到的SPM过量的原因。此处注意到的SPM升高似乎是由性别介导的，即仅在一种性别（雌性）中观察到。鉴于SS主要影响女性（约90%的确诊病例），这些结果可能为观察到的性别二态性背后的机制提供一些见解。
