Anti-Inflammatory Benefits of Antibiotics: Tylvalosin Induces Apoptosis of Porcine Neutrophils and Macrophages, Promotes Efferocytosis, and Inhibits Pro-Inflammatory CXCL-8, IL1α, and LTB4 Production, While Inducing the Release of Pro-Resolving Lipoxin A4 and Resolvin D1

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.

Polymyxin-Induced Cell Death of Human Macrophage-Like THP-1 and Neutrophil-Like HL-60 Cells Associated with the Activation of Apoptotic Pathways

“…Apoptosis is a form of programmed cell death that has a key role in immune regulation, as controlling the death of immune cells is essential for preventing the destruction of healthy tissues (30). Several antibiotics are able to modulate apoptosis signals in macrophages and neutrophils, which consequently affect both the host and pathogen (33)(34)(35)(36). The regulatory role of apoptosis is significant for the immune response, and disturbances of apoptosis in macrophages and neutrophils have been linked with serious clinical conditions (28,(37)(38)(39).…”

Helminth Interactions with Bacteria in the Host Gut Are Essential for Its Immunomodulatory Effect

“…However, this may be consistent with the study by Ozkul et al [ 72 ], which found that mice intestinal cells had a high susceptibility to apoptosis after antibiotic and subsequent DSS-colitis treatment. Furthermore, the use of antibiotics alone may have a non-antibiotic effect due to neutrophil apoptosis [ 73 ].…”

Evaluation of the clinical efficacy of a water soluble formulation of tylvalosin in the control of enzootic pneumonia associated with Mycoplasma hyopneumoniae and Pasteurella multocida in pigs

“…A disconnect between MIC and clinical efficacy has been previously reported for macrolides against respiratory pathogens in calves and swine [16,17] and this disconnect is reinforced by data presented here. Furthermore, it is well known that macrolides, including tylvalosin, have immunomodulatory effects which may impact in vivo efficacy [18,19]. Increasing evidence demonstrates that tylvalosin exerts such effects by increasing the apoptosis of porcine neutrophils and macrophages, increasing the release of Lipoxin A4 and Resolvin D1, while inhibiting the production and release of pro-inflammatory Leukotriene B4, Interleukin-8 and Interleukin-1α [18].…”

“…Furthermore, it is well known that macrolides, including tylvalosin, have immunomodulatory effects which may impact in vivo efficacy [18,19]. Increasing evidence demonstrates that tylvalosin exerts such effects by increasing the apoptosis of porcine neutrophils and macrophages, increasing the release of Lipoxin A4 and Resolvin D1, while inhibiting the production and release of pro-inflammatory Leukotriene B4, Interleukin-8 and Interleukin-1α [18]. These highly complex interactions may have aided the fight against disease.…”