Lipoxins, Aspirin-Triggered Epi-Lipoxins, Lipoxin Stable Analogues, and the Resolution of Inflammation

Abstract

Abstract. Lipoxins (LX) are eicosanoids with antiinflammatory activity in glomerulonephritis (GN) and inflammatory diseases, hypersensitivity, and ischemia reperfusion injury. It has been demonstrated that LXA 4 stimulates non-phlogistic phagocytosis of apoptotic polymorphonuclear neutrophils (PMN) by monocyte-derived macrophages (M) in vitro, suggesting a role for LX as endogenous pro-resolution lipid mediators. It is here reported that LXA 4 , LXB 4 , the aspirin-triggered LX (ATL) epimer, 15-epi-LXB 4 , and a stable synthetic analogue 15(R/S)-methyl-LXA 4 stimulate phagocytosis of exogenously administered excess apoptotic PMN by macrophages (M) in vivo in a classic model of acute inflammation, namely thioglycollate-induced peritonitis. Significant enhancement of phagocytosis in vivo was observed with 15-min exposure to LX and with intraperitoneal doses of LXA 4 , LXB 4 , 15(R/S)-methyl-LXA 4 , and 15-epi-LXB 4 of 2.5 to 10 g/kg. Non-phlogistic LX-stimulated phagocytosis by M was sensitive to inhibition of PKC and PI 3-kinase and associated with increased production of transforming growth factor-␤ 1 (TGF-␤ 1 ). LX-stimulated phagocytosis was not inhibited by phosphatidylserine receptor (PSR) antisera and was abolished by prior exposure of M to ␤1,3-glucan, suggesting a novel M-PMN recognition mechanism. Interestingly, the recently described peptide agonists of the LXA 4 receptor (MYFINITL and LESI-FRSLLFRVM) stimulated phagocytosis through a process associated with increased TGF-␤ 1 release. These data provide the first demonstration that LXA 4 , LXB 4 , ATL, and LX stable analogues rapidly promote M phagocytosis of PMN in vivo and support a role for LX as rapidly acting, proresolution signals in inflammation. Engagement of the LXR by LX generated during cell-cell interactions in inflammation and by endogenous LXR peptide agonists released from distressed cells may be an important stimulus for clearance of apoptotic cells and may be amenable to pharmacologic mimicry for therapeutic gain.Rapid, efficient and tightly regulated recruitment and clearance of polymorphonuclear neutrophil (PMN) at sites of inflammation are essential components of effective host defense. Evidence from in vitro models and from histopathology suggests that tissue damage mediated by PMN is limited by apoptosis and subsequent phagocytosis of the apoptotic PMN by macrophages (M) and "nonprofessional" phagocytes (1). A direct role for PMN in tissue injury in inflammation and ischemia reperfusion injury of the kidney and other organs is well established (2). Impaired clearance of apoptotic cells by M has been implicated in the pathogenesis of chronic inflammatory conditions, including glomerulonehritis (GN) and systemic lupus erythematosus (SLE) (3). The endogenous signals that promote clearance of apoptotic PMN from an inflammatory focus are still being defined. By dissecting out the mediator systems that regulate this process, it may be possible to design new pro-resolution strategies for inflammatory diseases.Lipoxins (LX), an acronym for...

Aspirin-Triggered Lipoxins Override the Apoptosis-Delaying Action of Serum Amyloid A in Human Neutrophils: A Novel Mechanism for Resolution of Inflammation

“…By contrast, LXA 4 was reported to stimulate fibroblast apoptosis (48), suggesting cell-specific lipoxin actions. Previous studies reported that LXA 4 and 15-epi-LXA 4 facilitate phagocytosis of apoptotic PMN by macrophages rather than interfering directly with the PMN apoptotic machinery (27,49). Our results show, for the first time, that an endogenous anti-inflammatory molecule aspirin-triggered 15-epi-LXA 4 can override a powerful antiapoptosis signal from SAA, thus profoundly affecting the fate of human PMN.…”

Murine Macrophages Produce Secretory Leukocyte Protease Inhibitor During Clearance of Apoptotic Cells: Implications for Resolution of the Inflammatory Response

“…Thus, the increased expression of TNF-␣, TGF-␤, and IL-10 may serve as regulatory mediators for inflammatory responses in the thymus after administration of anti-CD3 Ab. Two recent studies indicated that noninflammatory clearance of apoptotic cells could be regulated by anti-inflammatory lipid mediators (48,49). Our findings suggest SLPI can also participate in the resolution of inflammatory responses.…”

Elevated Expressions of 15-Lipoxygenase and Lipoxin A4 in Children with Acute Poststreptococcal Glomerulonephritis

“…27 In addition, LXA 4 and its analogue activate monocytes and promote phagocytosis of apoptotic PMNs by macrophages without proinflammatory cytokine release. 28 The engulfment of apoptotic PMNs leads to the expression of 15-LO in macrophages that released LXA 4 to limit inflammation further by stopping PMN influx and accelerating the macrophage removal of apoptotic PMNs, 29 suggesting that LXA 4 may be involved in the dynamic regulation of the resolution phase of APSGN. Consistently, in the current study, glomerular 15-LO expression was up-regulated in the resolution phase of disease ( Figure 5, B and C).…”