Wu Yanling, Dahlgren Claes, Forsman Huamei, Sundqvist Martina
Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
Prostaglandins Leukot Essent Fatty Acids. 2025 Apr 3;205:102680. doi: 10.1016/j.plefa.2025.102680.
The endogenous neutrophil chemoattractant leukotriene B (LTB) is a biased signalling agonist that potently increases the intracellular concentration of free calcium ions ([Ca]), but alone is a weak activator of the neutrophil superoxide anion (O)-generating NADPH oxidase. However, in this study we show that an allosteric modulator of the free fatty acid 2 receptor (FFA2R) converts LTB into a potent NADPH oxidase activating agonist. While an allosteric modulation of FFA2R was required for LTB receptor 1 (BLTR)-mediated activation of the NADPH oxidase, the LTB-induced increase in [Ca] was not affected by the modulator. Thus, the biased BLTR signalling pattern was altered in the presence of the allosteric FFA2R modulator, being biased with a preference towards the signals that activate the NADPH oxidase relative to an increase in [Ca]. Both BLTR and FFA2R belong to the family of G protein-coupled receptors (GPCRs), and our results show that a communication between the activated BLTR and the allosterically modulated FFA2Rs generates signals that induce NADPH oxidase activity. This is consistent with a previously described receptor transactivation (crosstalk) model whereby the function of one neutrophil GPCR can be regulated by receptor downstream signals generated by another GPCR. Furthermore, the finding that an allosteric FFA2R modulator sensitises not only the response induced by orthosteric FFA2R agonists but also the response induced by LTB, violates the receptor restriction properties that normally define the selectivity of allosteric GPCR modulators.
内源性中性粒细胞趋化因子白三烯B（LTB）是一种偏向性信号激动剂，能有效提高细胞内游离钙离子（[Ca]）的浓度，但单独作用时是中性粒细胞超氧阴离子（O）生成的NADPH氧化酶的弱激活剂。然而，在本研究中我们表明，游离脂肪酸2受体（FFA2R）的变构调节剂可将LTB转化为强效的NADPH氧化酶激活激动剂。虽然FFA2R的变构调节是LTB受体1（BLTR）介导的NADPH氧化酶激活所必需的，但LTB诱导的[Ca]升高不受该调节剂影响。因此，在变构FFA2R调节剂存在的情况下，偏向性的BLTR信号模式发生了改变，相对于[Ca]升高，偏向于激活NADPH氧化酶的信号。BLTR和FFA2R都属于G蛋白偶联受体（GPCR）家族，我们的结果表明，激活的BLTR与变构调节的FFA2R之间的通讯产生了诱导NADPH氧化酶活性的信号。这与先前描述的受体反式激活（串扰）模型一致，即一种中性粒细胞GPCR的功能可由另一种GPCR产生的受体下游信号调节。此外，变构FFA2R调节剂不仅能使正构FFA2R激动剂诱导的反应敏感化，还能使LTB诱导的反应敏感化，这一发现违背了通常定义变构GPCR调节剂选择性的受体限制特性。
