New maresin conjugates in tissue regeneration pathway counters leukotriene D₄–stimulated vascular responses

Abstract

Resolution of acute inflammation is governed, in part, by lipid mediator class switching from proinflammatory eicosanoids to specialized proresolving mediators, including a recently identified new pathway of mediators, termed maresin conjugates in tissue regeneration (MCTR), which includes MCTR1, MCTR2, and MCTR3. Here, we addressed whether each MCTR can impact the known vascular actions of cysteinyl leukotrienes. Leukotriene D (LTD; 1.5 nmol/mouse) initiated vascular leakage in mouse cremaster vessels, which was reduced (>75%) by MCTR1 and MCTR2 (0.15 nmol each). With isolated Ciona intestinalis (sea squirt) primordial hearts, LTD (1-100 nM) induced negative inotropic action and lowered heartbeats 20-30%. Each MCTR (1-100 nM) prevented LTD-reduced heart rates. With human cysteinyl leukotriene receptor-1 (CysLT1) expressed in CHO cells, each MCTR (10-100 nM) significantly reduced LTD-initiated signaling. To assess the contribution of CysLT1 in the proresolving actions of MCTR, we carried out human macrophage (MΦ) phagocytosis. Each MCTR (0.1-10 nM) stimulated human MΦ phagocytosis of live Escherichia coli, whereas LTD did not stimulate phagocytosis. MCTR-activated phagocytosis was significantly blocked by a pharmacologic receptor antagonist (MK571). With both CHO-CysLT1 and human MΦs, each MCTR competed for specific [H]-LTD binding with apparent lower affinity than LTD. Thus, each MCTR functionally interacts with human CysLT1 to pharmacologically counter-regulate vascular responses and stimulate physiologic phagocytosis with MΦs.-Chiang, N., Riley, I. R., Dalli, J., Rodriguez, A. R., Spur, B. W., Serhan, C. N. New maresin conjugates in tissue regeneration pathway counters leukotriene D-stimulated vascular responses.

Cysteinyl maresins regulate the prophlogistic lung actions of cysteinyl leukotrienes

“…MCTRs (0.1-10 nmol/L) also stimulate human macrophage phagocytosis, a proresolving action blocked by CysLT receptor antagonism. 18 The present results are the first for human lung tissue, in which MCTRs each reduced LTD 4 -stimulated human airway narrowing.…”

“…Of note, MCTR inhibition of LTD 4 was partially antagonized by the receptor antagonist (Fig 2, C and D), which is in line with MCTR interactions with CysLT receptors in model systems. 18 LTD 4 -induced airway contraction was concentration dependent (1-100 nmol/L; Fig 2, E). Individual MCTRs blocked LTD 4 -mediated contraction with a rank order potency of MCTR3 > MCTR2 ; MCTR1 (Fig 2, E).…”

“…7,8 As demonstrated recently in specific binding studies, MCTR1, MCTR2, and MCTR3 compete for specific tritiated LTD 4 binding to human recombinant CysLT1 with apparent lower affinity than LTD 4 18 and reduce LTD 4 -mediated intracellular signaling. 18 The relatively lower affinity of MCTRs to CysLT1 compared with LTD 4 suggests that MCTRs can signal through other CysLT-specific receptors, such as GPR99, an LTE 4 receptor, 25,26 and high-affinity MCTR-specific receptors that are yet to be uncovered. MCTRs (0.1-10 nmol/L) also stimulate human macrophage phagocytosis, a proresolving action blocked by CysLT receptor antagonism.…”

“…[10][11][12][13][14][15] These chemical mediator pathways give rise to unique bioactive structures that include maresin conjugates in tissue regeneration (MCTRs; Fig 1, A), protectin conjugates in tissue regeneration (PCTRs), and resolvin conjugates in tissue regeneration. [10][11][12]16,17 Of interest, recent results showed that MCTRs compete with LTD 4 binding on recombinant CysLT1, 18 thus warranting their investigation in mammalian tissues. Here we report that MCTRs are major bioactive chemical mediators produced by the human lung that counterregulate CysLTs in tissue homeostasis and resolution of complex immune responses.…”

Unified nexus of macrophages and maresins in cardiac reparative mechanisms

“…With the significant roles of MaR-1 in regulating phagocytic functions, tissue regeneration, and wound healing properties, it can be used as a therapeutic agent, as it impedes the rate of inflammation during atherosclerosis by limiting the preferential synthesis of LTB 4 by inhibiting the production of PGE 2 . MaR-1 can also be employed as a therapeutic target as MCTR-1, -2 and -3 ( Table 2) conjugates derived from MaR-1 counter both vascular and negative inotropic actions that are stimulated by LTD 4 , by blocking the MK571 receptor in tissue regeneration (107).…”