Nonantibiotic macrolides restore airway macrophage phagocytic function with potential anti-inflammatory effects in chronic lung diseases

Abstract

We reported defective efferocytosis associated with cigarette smoking and/or airway inflammation in chronic lung diseases, including chronic obstructive pulmonary disease, severe asthma, and childhood bronchiectasis. We also showed defects in phagocytosis of nontypeable (NTHi), a common colonizer of the lower airway in these diseases. These defects could be substantially overcome with low-dose azithromycin; however, chronic use may induce bacterial resistance. The aim of the present study was therefore to investigate two novel macrolides-2'-desoxy-9-(S)-erythromycylamine (GS-459755) and azithromycin-based 2'-desoxy molecule (GS-560660)-with significantly diminished antibiotic activity against, ,, and We tested their effects on efferocytosis, phagocytosis of NTHi, cell viability, receptors involved in recognition of apoptotic cells and/or NTHi (flow cytometry), secreted and cleaved intracellular IL-1β (cytometric bead array, immunofluorescence/confocal microscopy), and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) using primary alveolar macrophages and THP-1 macrophages ± 10% cigarette smoke extract. Dose-response experiments showed optimal prophagocytic effects of GS-459755 and GS-560660 at concentrations of 0.5-1 µg/ml compared with our findings with azithromycin. Both macrolides significantly improved phagocytosis of apoptotic cells and NTHi (e.g., increases in efferocytosis and phagocytosis of NTHi: GS-459755, 23 and 22.5%, = 0.043; GS-560660, 23.5 and 22%, = 0.043, respectively). Macrophage viability remained>85% following 24 h exposure to either macrolide at concentrations up to 20 µg/ml. Secreted and intracellular-cleaved IL-1β was decreased with both macrolides with no significant changes in recognition molecules c-mer proto-oncogene tyrosine kinase; scavenger receptor class A, member 1; Toll-like receptor 2/4; or CD36. Particulate cytoplasmic immunofluorescence of NLRP3 inflammasome was also reduced significantly. We conclude that GS-459755 and GS-560660 may be useful for reducing airway inflammation in chronic lung diseases without inducing bacterial resistance.

Macrolide derivatives reduce proinflammatory macrophage activation and macrophage‐mediated neurotoxicity

“…In the spinal cord injury patient population, for example, AZM is the antibiotic of choice for treating recurrent respiratory infections and pneumonia, a leading cause of death following spinal cord injury; thus, antibiotic resistance is a major concern. Fortunately, recent studies have indicated that macrolides modified to remove their antibacterial activity retain beneficial anti‐inflammatory effects in models of inflammatory skin disorders and chronic lung diseases …”

“…After 30 minutes, 10 mL of methanol and 10 mL saturated (d, J = 6.6 Hz, 3H), 0.87 (dd, J = 8.4, 6.5 Hz, 3H). 13 0.99 (dd, J = 13.7, 6.9 Hz, 3H), 0.88 (q, J = 7.5 Hz, 3H). 13…”

“…In efforts to improve efficacy and/or reduce the risk of increasing antibiotic resistance, researchers are evaluating the immunomodulatory potential of AZM derivatives and other macrolide derivatives with the goal of separating the antibiotic from immunomodulatory properties. As a result, some macrolide derivatives have been shown to retain immunomodulatory properties in models of lung inflammation, inflammatory bowel diseases, arthritis, and skin inflammation . The ability of macrolide derivatives to reduce macrophage‐mediated neurotoxicity, however, is unknown.…”

“…As a result, some macrolide derivatives have been shown to retain immunomodulatory properties in models of lung inflammation, inflammatory bowel diseases, arthritis, and skin inflammation. [13][14][15][16][17][18] The ability of macrolide derivatives to reduce macrophage-mediated neurotoxicity, however, is unknown. With the increased use of AZM as an immunomodulatory agent for macrophage-mediated neurotoxicity in CNS pathologies, our goal in the present study was to determine whether macrolide derivatives retain neuroprotective properties.…”

Protein S and Gas6 induce efferocytosis of HIV-1-infected cells

“…Some of this phagocytosis is likely mediated by efferocytosis (Akbar et al, 1994). Because Mer has been shown to be expressed on human monocytes and tissue macrophages, including alveolar macrophages, macrophages in the liver and in mesenteric lymph nodes, and microglia (Bernsmeier et al, 2015; Zhu et al, 2014; Hodge et al, 2017; Kazeros et al, 2008; Healy et al, 2016), it would be of interest to investigate whether PtdSer/protein S/Mer mediates efferocytosis of SIV and/or HIV-1-infected cells and contributes to the amounts of viral DNA and proteins detected in macrophages in vivo .…”