Identification and Actions of a Novel Third Maresin Conjugate in Tissue Regeneration: MCTR3

Abstract

Maresin conjugates in tissue regeneration (MCTR) are a new family of evolutionarily conserved chemical signals that orchestrate host responses to promote tissue regeneration and resolution of infections. Herein, we identified the novel MCTR3 and established rank order potencies and matched the stereochemistries of MCTR1, MCTR2 and MCTR3 using material prepared by total organic synthesis and mediators isolated from both mouse and human systems. MCTR3 was produced from endogenous substrate by E. coli activated human macrophages and identified in sepsis patients. Each of the three synthetic MCTR dose-dependently (1–100nM) accelerated tissue regeneration in planaria by 0.6–0.9 days. When administered at the onset or peak of inflammation, each of the MCTR promoted resolution of E. coli infections in mice. They increased bacterial phagocytosis by exudate leukocytes (~15–50%), limited neutrophil infiltration (~20–50%), promoted efferocytosis (~30%) and reduced eicosanoids. MCTR1 and MCTR2 upregulated human neutrophil and macrophage phagocytic responses where MCTR3 also proved to possess potent actions. These results establish the complete stereochemistry and rank order potencies for MCTR1, MCTR2 and MCTR3 that provide novel resolution moduli in regulating host responses to clear infections and promote tissue regeneration.

Maresin conjugates in tissue regeneration biosynthesis enzymes in human macrophages

“…Each of these molecules was identified in accordance with published criteria (4,14), including matching retention times and MS-MS spectra (Fig. 1).…”

“…This mediator is then a precursor in the biosynthesis of MCTR3, where in human macrophages the cysteinyl-glycinyl bond is cleaved by a dipeptidase enzyme. Using LM metabololipidomics, we profiled human tissues identifying MCTR in human plasma, serum, and lymph nodes at concentrations (0.5-4.5 pM) commensurate with their known bioactive ranges (4,14).…”

“…Classic macrophages express higher levels of inflammation-initiating eicosanoids, whereas alternatively activated cells display higher levels of proresolving mediators (6,13). Recently, we reported that macrophages produce a family of bioactive peptide-conjugated mediators coined maresin conjugates in tissue regeneration (MCTR) (4) (14). Each displays potent bioactions in stimulating human phagocyte functions, promotes the resolution of bacterial infections, counterregulates the production of proinflammatory mediators, and promotes tissue repair and regeneration (14).…”

Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors

“…Continued investigation along these lines permitted elucidation of three separate pathways, coined MCTRs, PCTRs and RCTRs. The stereochemistry of MCTR1, MCTR2 and MCTR3 and PCTR1 (Dalli et al, 2016a; Ramon et al, 2016) are established (Figure 2), and they are produced in mouse lymphoid tissues and in infectious inflammatory exudates as well as in specific human tissues (Dalli et al, 2017a). …”

Pharmacological Targeting of the Host–Pathogen Interaction: Alternatives to Classical Antibiotics to Combat Drug-Resistant Superbugs

“…Administration of a synthetic protectin enhanced macrophage recruitment, phagocytosis of E. coli , while decreasing neutrophil infiltration, promoting efferocytosis of dead cells, and blunting production of pro-inflammatory lipid mediators [62]. Likewise, maresins and resolvins promote resolution of experimental murine E. coli or S. aureus infections, respectively, by increasing macrophage phagocytosis and efferocytosis while limiting neutrophil and eicosanoid production [63, 64]. Additional compounds, termed 13-series resolvins, were recently identified from neutrophil-endothelial co-cultures as a product of cyclooxygenase-2 (COX-2) activity, further induced by atorvastatin via S-notrosylation of COX-2, and present in human tissues after sterile inflammation or infection.…”