The Protectin PCTR1 Is Produced by Human M2 Macrophages and Enhances Resolution of Infectious Inflammation

Abstract

Inflammation and its natural resolution are host-protective responses triggered by infection or injury. The resolution phase of inflammation is regulated by enzymatically produced specialized pro-resolving mediators. We recently identified a new class of peptide-conjugated specialized pro-resolving mediators that carry potent tissue regenerative actions that belong to the protectin family and are coined protectin conjugates in tissue regeneration (PCTR). Herein, with the use of microbial-induced peritonitis in mice and liquid chromatography-tandem mass spectrometryebased lipid mediator metabololipidomics, we found that PCTR1 is temporally regulated during self-resolving infection. When administered at peak of inflammation, PCTR1 enhanced macrophage recruitment and phagocytosis of Escherichia coli, decreased polymorphonuclear leukocyte infiltration, and counter-regulated inflammation-initiating lipid mediators, including prostaglandins. In addition, biologically produced PCTR1 promoted human monocyte and macrophage migration in a dose-dependent manner (0.001 to 10.0 nmol/L). We prepared PCTR1 via organic synthesis and confirmed that synthetic PCTR1 increased macrophage and monocyte migration, enhanced macrophage efferocytosis, and accelerated tissue regeneration in planaria. With human macrophage subsets, PCTR1 levels were significantly higher in M2 macrophages than in M1 phenotype, along with members of the resolvin conjugates in tissue regeneration and maresin conjugate families. In contrast, M1 macrophages gave higher levels of cysteinyl leukotrienes. Together, these results demonstrate that PCTR1 is a potent monocyte/macrophage agonist, regulating key anti-inflammatory and pro-resolving processes during bacterial infection. (Am J Pathol 2016, 186: 962e973; http://dx

Maresin conjugates in tissue regeneration biosynthesis enzymes in human macrophages

“…1). We then assessed their amounts in relation to other peptide-conjugated lipid mediators, namely the cysteinyl leukotrienes (7) and protectin conjugates in tissue regeneration (PCTR) (6). MCTR levels in human serum and plasma demonstrated that serum contained significantly higher levels of MCTR1 and MCTR2 (Fig.…”

“…Recent evidence also demonstrates that lipid mediator profiles change with macrophage phenotype. 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).…”

“…Central to the regulation of resolution responses is a novel genus of endogenous mediators termed specialized proresolving mediators (SPM) (2). They actively counterregulate production of inflammation-initiating signals including cytokines, chemokines, and lipid mediators and regulate leukocyte trafficking and phenotype as well as promote tissue repair and regeneration (1,2,(4)(5)(6). At the site of inflammation leukocytes are key in the production of both inflammation-initiating (7,8) and proresolving mediators (2, 4) because they carry the necessary enzymatic machinery for the stereoselective conversion of precursor essential fatty acids to the bioactive mediators.…”

Macrophage functions in lean and obese adipose tissue

“…Protectin is synthesized by M2 macrophages and is involved with the resolution of inflammation and tissue healing 19 . M2 macrophages express lower levels of inflammatory cytokines and higher levels anti-inflammatory cytokines such as IL-10, IL-1RA.…”

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

“…Protectins, naturally produced by human M2 macrophages, enhance resolution of inflammation cause by infection. 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].…”