Abstract
Excessive accumulation of neutrophils and their uncontrolled death by necrosis at the site of inflammation exacerbates inflammatory responses and leads to self-amplifying tissue injury and loss of organ function, as exemplified in a variety of respiratory diseases. In homeostasis, neutrophils are inactivated by apoptosis, and non phlogistically removed by neighboring macrophages in a process known as efferocytosis, which promotes the resolution of inflammation. The present study assessed the potential anti-inflammatory and pro-resolution benefits of tylvalosin, a recently developed broad-spectrum veterinary macrolide derived from tylosin. Recent findings indicate that tylvalosin may modulate inflammation by suppressing NF-κB activation. Neutrophils and monocyte-derived macrophages were isolated from fresh blood samples obtained from 12- to 22-week-old pigs. Leukocytes exposed to vehicle or to tylvalosin (0.1, 1.0, or 10 µg/mL; 0.096–9.6 µM) were assessed at various time points for apoptosis, necrosis, efferocytosis, and changes in the production of cytokines and lipid mediators. The findings indicate that tylvalosin increases porcine neutrophil and macrophage apoptosis in a concentration- and time-dependent manner, without altering levels of necrosis or reactive oxygen species production. Importantly, tylvalosin increased the release of pro-resolving Lipoxin A4 (LXA4) and Resolvin D1 (RvD1) while inhibiting the production of pro-inflammatory Leukotriene B4 (LTB4) in Ca2+ ionophore-stimulated porcine neutrophils. Tylvalosin increased neutrophil phospholipase C activity, an enzyme involved in releasing arachidonic acid from membrane stores. Tylvalosin also inhibited pro-inflammatory chemokine (C–X–C motif) ligand 8 (CXCL-8, also known as Interleukin-8) and interleukin-1 alpha (IL-1α) protein secretion in bacterial lipopolysaccharide-stimulated macrophages. Together, these data illustrate that tylvalosin has potent immunomodulatory effects in porcine leukocytes in addition to its antimicrobial properties.
Highlights
The resolution of inflammation is critical for the restoration of homeostasis following infection or tissue injury [1,2,3,4]
Using tylvalosin and porcine leukocytes as a model system, the present findings demonstrate that an antibiotic may promote neutrophil apoptosis and efferocytosis, and inhibit pro-inflammatory leukotriene B4 (LTB4) production while inducing the synthesis of LXA4 and resolvin D1 (RvD1) independently of its antimicrobial actions
Caspase-3 cleavage, which leads to DNA fragmentation during apoptosis, was significantly greater in tylvalosin-treated porcine neutrophils versus controls (Figure 1)
Summary
The resolution of inflammation is critical for the restoration of homeostasis following infection or tissue injury [1,2,3,4]. Actinobacillus pleuropneumoniae colonize the lungs of swine and release leukotoxins, which in turn lyse neutrophils and macrophages [5,6,7,8] This promotes self-perpetuating inflammation [2,3,4, 7], as activated leukocytes release more pro-inflammatory mediators, including IL-1α, IL-1β, IL-6, CXCL-8 (synonymous with IL-8), and leukotriene B4 [9,10,11,12]. Lipoxins have dual anti-inflammatory and pro-resolution properties such as increasing efferocytosis while inducing the production of anti-inflammatory IL-10, as well as decreasing pro-inflammatory cytokines and acting as analgesics [20, 24,25,26,27] This family of lipid mediators is generated via 15-lipoxygenase signaling from arachidonic acid, and 15(S)-HETE precursors [20, 24, 27]. Researchers both in human and veterinary medicine have been screening for therapeutics that may halt self-perpuating inflammation by stimulating antiinflammatory and/or pro-resolution mediators [13, 32,33,34]
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