TAM receptors are dispensable in the phagocytosis and killing of bacteria

Williams, Julie C.; Craven, Robin R.; Earp, H. Shelton; Kawula, Tom; Matsushima, Glenn K.

doi:10.1016/j.cellimm.2009.06.006

Cited by 16 publications

(10 citation statements)

References 26 publications

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“…In the present study, we further investigated the effects of azithromycin, GS-459755, and GS-560660 on receptors that may mediate binding and internalization of either bacteria or apoptotic cells: MerTK (involved in engulfment of the tethered apoptotic cell; increased expression has been reported on airway macrophages from cigarette smokers) (14), SRA-1 (significantly underexpressed in COPD airways) (24,29), and TLR2 and -4 (lipidrecognizing molecules). Despite the potential importance of these receptors and a report that clarithromycin downregulated TLR4 expression on monocytes (30), no significant changes were noted in the presence of azithromycin, GS-459755, or GS-560660, suggesting that the mechanisms of action of macrolide antibiotics do not involve significant changes to these molecules involved in the recognition of apoptotic cells or NTHi. It was previously reported that azithromycin shifted the polarization of a mouse macrophage cell line toward an alternatively activated "M2" phenotype (17).…”

Section: L684mentioning

confidence: 78%

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

Hodge

Tran

Hamon

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

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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.

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Section: L684mentioning

confidence: 78%

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

Hodge

Tran

Hamon

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Monocytes and macrophages, two important phagocytes, use surface receptors to perform phagocytic uptake of apoptotic cells. The TAM-receptor tyrosine kinase family consists of three phagocytic receptors: Tyro3, Axl and Mer [ 6 ] and are key to apoptotic cell clearance [ 7 ] but not required for phagocytosis of bacteria [ 8 ]. They recognise the apoptotic cell surface membrane marker phosphatidylserine through two bridging molecules, protein S (ProS) and “a product of growth arrest-specific gene 6” (Gas6).…”

Section: Introductionmentioning

confidence: 99%

Increased soluble phagocytic receptors sMer, sTyro3 and sAxl and reduced phagocytosis in Juvenile-onset Systemic Lupus Erythematosus

et al. 2015

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BackgroundThe TAM-receptor tyrosine kinase family, Tyro3, Axl and Mer are key to apoptotic cell clearance. Reduced phagocytic clearance in systemic lupus erythematosus (SLE) leads to prolonged exposure of nuclear autoantigen to the immune system. Here we measure the levels of TAM receptors and the phagocytic capacity of monocytes and macrophages in juvenile-onset SLE (JSLE).MethodMer protein was measured on monocytes from JSLE, healthy control and JIA patients. JSLE, healthy control and JIA patients’ plasma were analysed for soluble Mer (sMer), soluble Tyro3 (sTyro) and soluble Axl (sAxl). A phagocytosis assay measured the effect of JSLE serum on phagocytic potential of JSLE and control monocytes to engulf E. Coli bacteria and healthy macrophages to engulf apoptotic neutrophils.ResultsMer receptor expression was significantly decreased on JSLE monocytes compared to healthy controls. Plasma sMer, sTyro and sAxl were significantly increased in JSLE patients compared to controls (p < 0.05). Adult healthy control macrophages had significantly decreased phagocytosis of E. Coli and apoptotic neutrophils in the presence of 10% JSLE serum compared to control serum (p < 0.05).ConclusionJSLE patients have a decreased phagocytosis due to both serum and cell-derived factors. Significantly increased levels of sMer, sTyro3 and sAxl may be important factors contributing to the deficit in phagocytosis ability.

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“…74,83 However, viral entry into target cells is facilitated by Axl by apoptotic mimicry of the viral envelope. 84 Recently, new ligands for TAM receptor-mediated efferocytosis have been described: Tubby, tubby-like protein 1 (Tulp1), 85 and galectin-3.…”

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confidence: 99%

TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis

Meer

Poll

Veer

2014

Blood

283

228

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TAM receptors (Tyro3, Axl, and Mer) belong to a family of receptor tyrosine kinases that have important effects on hemostasis and inflammation. Also, they affect cell proliferation, survival, adhesion, and migration. TAM receptors can be activated by the vitamin K–dependent proteins Gas6 and protein S. Protein S is more commonly known as an important cofactor for protein C as well as a direct inhibitor of multiple coagulation factors. To our knowledge, the functions of Gas6 are limited to TAM receptor activation. When activated, the TAM receptors have effects on primary hemostasis and coagulation and display an anti-inflammatory or a proinflammatory effect, depending on cell type. To comprehend the effects that the TAM receptors and their ligands have on hemostasis and inflammation, we compare studies that report the different phenotypes displayed by mice with deficiencies in the genes of this receptor family and its ligands (protein S+/−, Gas6−/−, TAM−/−, and variations of these). In this manner, we aim to display which features are attributable to the different ligands. Because of the effects TAM receptors have on hemostasis, inflammation, and cancer growth, their modulation could make interesting therapeutic targets in thromboembolic disease, atherosclerosis, sepsis, autoimmune disease, and cancer.

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TAM receptors are dispensable in the phagocytosis and killing of bacteria

Cited by 16 publications

References 26 publications

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

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

Increased soluble phagocytic receptors sMer, sTyro3 and sAxl and reduced phagocytosis in Juvenile-onset Systemic Lupus Erythematosus

TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis

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