Ruby Fernandez-Boyanapalli

Publications (5)29.62 Total impact

• Source

  Available from: Brian J Day

  Article: Obesity impairs apoptotic cell clearance in asthma.

  Ruby Fernandez-Boyanapalli, Elena Goleva, Christena Kolakowski, Elysia Min, Brian Day, Donald Y M Leung, David W H Riches, Donna L Bratton, E Rand Sutherland
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  ABSTRACT: BACKGROUND: Asthma in obese adults is typically more severe and less responsive to glucocorticoids than asthma in nonobese adults. OBJECTIVE: We sought to determine whether the clearance of apoptotic inflammatory cells (efferocytosis) by airway macrophages was associated with altered inflammation and reduced glucocorticoid sensitivity in obese asthmatic patients. METHODS: We investigated the relationship of efferocytosis by airway (induced sputum) macrophages and blood monocytes to markers of monocyte programming, in vitro glucocorticoid response, and systemic oxidative stress in a cohort of adults with persistent asthma. RESULTS: Efferocytosis by airway macrophages was assessed in obese (n = 14) and nonobese (n = 19) asthmatic patients. Efferocytosis by macrophages was 40% lower in obese than nonobese subjects, with a mean efferocytic index of 1.77 (SD, 1.07) versus 3.00 (SD, 1.25; P < .01). A similar reduction of efferocytic function was observed in blood monocytes of obese participants. In these monocytes there was also a relative decrease in expression of markers of alternative (M2) programming associated with efferocytosis, including peroxisome proliferator-activated receptor δ and CX3 chemokine receptor 1. Macrophage efferocytic index was significantly correlated with dexamethasone-induced mitogen-activated protein kinase phosphatase 1 expression (ρ = 0.46, P < .02) and baseline glucocorticoid receptor α expression (ρ = 0.44, P < .02) in PBMCs. Plasma 4-hydroxynonenal levels were increased in obese asthmatic patients at 0.33 ng/mL (SD, 0.15 ng/mL) versus 0.16 ng/mL (SD, 0.08 ng/mL) in nonobese patients (P = .006) and was inversely correlated with macrophage efferocytic index (ρ = -0.67, P = .02). CONCLUSIONS: Asthma in obese adults is associated with impaired macrophage/monocyte efferocytosis. Impairment of this anti-inflammatory process is associated with altered monocyte/macrophage programming, reduced glucocorticoid responsiveness, and systemic oxidative stress.
  The Journal of allergy and clinical immunology 11/2012; · 9.17 Impact Factor
• Source

  Available from: PubMed Central

  Article: Modulation of macrophage efferocytosis in inflammation.

  Darlynn Korns, S Courtney Frasch, Ruby Fernandez-Boyanapalli, Peter M Henson, Donna L Bratton
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  ABSTRACT: A critical function of macrophages within the inflammatory milieu is the removal of dying cells by a specialized phagocytic process called efferocytosis ("to carry to the grave"). Through specific receptor engagement and induction of downstream signaling, efferocytosing macrophages promote resolution of inflammation by (i) efficiently engulfing dying cells, thus avoiding cellular disruption and release of inflammatory contents, and (ii) producing anti-inflammatory mediators such as IL-10 and TGF-β that dampen pro-inflammatory responses. Evidence suggests that plasticity in macrophage programming, in response to changing environmental cues, modulates efferocytic capability. Essential to programming for enhanced efferocytosis is activation of the nuclear receptors PPARγ, PPARδ, LXR, and possibly RXRα. Additionally, a number of signals in the inflammatory milieu, including those from dying cells themselves, can influence efferocytic efficacy either by acting as immediate inhibitors/enhancers or by altering macrophage programming for longer-term effects. Importantly, sustained inflammatory programming of macrophages can lead to defective apoptotic cell clearance and is associated with development of autoimmunity and other chronic inflammatory disorders. This review summarizes the current knowledge of the multiple factors that modulate macrophage efferocytic ability and highlights emerging therapeutic targets with significant potential for limiting chronic inflammation.
  Frontiers in immunology. 01/2011; 2:57.
• Article: PPARγ activation normalizes resolution of acute sterile inflammation in murine chronic granulomatous disease.

  Ruby Fernandez-Boyanapalli, S Courtney Frasch, David W H Riches, R William Vandivier, Peter M Henson, Donna L Bratton
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  ABSTRACT: Absence of a functional nicotinamide adenine dinucleotide phosphate (NADPH) oxidase predisposes chronic granulomatous disease (CGD) patients to infection, and also to unexplained, exaggerated inflammation. The impaired recognition and removal (efferocytosis) of apoptotic neutrophils by CGD macrophages may contribute to this effect. We hypothesized that peroxisome proliferator-activated receptor γ (PPARγ) activation during CGD inflammation is deficient, leading to altered macrophage programming and decreased efferocytosis, and that PPARγ agonism would enhance resolution. using the gp91(phox-/-) murine model of X-linked CGD in a well-characterized model of sterile, zymosan-induced peritonitis, it was demonstrated that PPARγ expression and activation in CGD macrophages were significantly deficient at baseline, and acquisition was delayed over the course of inflammation relative to that of wild-type. Efferocytosis by macrophages reflected PPARγ activation during peritonitis and was impaired in CGD mice (versus wild-type), leading to accumulation of apoptotic neutrophils. Importantly, provision of the PPARγ agonist, pioglitazone, either prophylactically or during inflammation, significantly enhanced macrophage PPARγ-mediated programming and efferocytosis, reduced accumulation of apoptotic neutrophils, and normalized the course of peritonitis in CGD mice. As such, PPARγ may be a therapeutic target for CGD, and possibly other inflammatory conditions where aberrant macrophage programming and impaired efferocytosis delay resolution of inflammation.
  Blood 11/2010; 116(22):4512-22. · 9.90 Impact Factor
• Article: Impaired phagocytosis of apoptotic cells by macrophages in chronic granulomatous disease is reversed by IFN-γ in a nitric oxide-dependent manner.

  Ruby Fernandez-Boyanapalli, Kathleen A McPhillips, S Courtney Frasch, William J Janssen, Mary C Dinauer, David W H Riches, Peter M Henson, Aideen Byrne, Donna L Bratton
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  ABSTRACT: Immunodeficiency in chronic granulomatous disease (CGD) is well characterized. Less understood are exaggerated sterile inflammation and autoimmunity associated with CGD. Impaired recognition and clearance of apoptotic cells resulting in their disintegration may contribute to CGD inflammation. We hypothesized that priming of macrophages (Ms) with IFN-γ would enhance impaired engulfment of apoptotic cells in CGD. Diverse M populations from CGD (gp91(phox)(-/-)) and wild-type mice, as well as human Ms differentiated from monocytes and promyelocytic leukemia PLB-985 cells (with and without mutation of the gp91(phox)), demonstrated enhanced engulfment of apoptotic cells in response to IFN-γ priming. Priming with IFN-γ was also associated with increased uptake of Ig-opsonized targets, latex beads, and fluid phase markers, and it was accompanied by activation of the Rho GTPase Rac. Enhanced Rac activation and phagocytosis following IFN-γ priming were dependent on NO production via inducible NO synthase and activation of protein kinase G. Notably, endogenous production of TNF-α in response to IFN-γ priming was critically required for inducible NO synthase upregulation, NO production, Rac activation, and enhanced phagocytosis. Treatment of CGD mice with IFN-γ also enhanced uptake of apoptotic cells by M in vivo via the signaling pathway. Importantly, during acute sterile peritonitis, IFN-γ treatment reduced excess accumulation of apoptotic neutrophils and enhanced phagocytosis by CGD Ms. These data support the hypothesis that in addition to correcting immunodeficiency in CGD, IFN-γ priming of Ms restores clearance of apoptotic cells and may thereby contribute to resolution of exaggerated CGD inflammation.
  The Journal of Immunology 10/2010; 185(7):4030-41. · 5.79 Impact Factor
• Article: NADPH oxidase-dependent generation of lysophosphatidylserine enhances clearance of activated and dying neutrophils via G2A.

  S Courtney Frasch, Karin Zemski Berry, Ruby Fernandez-Boyanapalli, Hyun-Sun Jin, Christina Leslie, Peter M Henson, Robert C Murphy, Donna L Bratton
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  ABSTRACT: Exofacial phosphatidylserine (PS) is an important ligand mediating apoptotic cell clearance by phagocytes. Oxidation of PS fatty acyl groups (oxPS) during apoptosis reportedly mediates recognition through scavenger receptors. Given the oxidative capacity of the neutrophil NADPH oxidase, we sought to identify oxPS signaling species in stimulated neutrophils. Using mass spectrometry analysis, only trace amounts of previously characterized oxPS species were found. Conversely, 18:1 and 18:0 lysophosphatidylserine (lyso-PS), known bioactive signaling phospholipids, were identified as abundant modified PS species following activation of the neutrophil oxidase. NADPH oxidase inhibitors blocked the production of lyso-PS in vitro, and accordingly, its generation in vivo by activated, murine neutrophils during zymosan-induced peritonitis was absent in mice lacking a functional NADPH oxidase (gp91phox-/-). Treatment of macrophages with lyso-PS enhanced the uptake of apoptotic cells in vitro, an effect that was dependent on signaling via the macrophage G2A receptor. Similarly, endogenously produced lyso-PS also enhanced the G2A-mediated uptake of activated PS-exposing (but non-apoptotic) neutrophils, raising the possibility of non-apoptotic mechanisms for removal of inflammatory cells during resolution. Finally, antibody blockade of G2A signaling in vivo prolonged zymosan-induced neutrophilia in wild-type mice, whereas having no effect in gp91phox-/- mice where lyso-PS are not generated. Taken together, we show that lyso-PS are modified PS species generated following activation of the NADPH oxidase and lyso-PS signaling through the macrophage G2A functions to enhance existing receptor/ligand systems for optimal resolution of neutrophilic inflammation.
  Journal of Biological Chemistry 10/2008; 283(48):33736-49. · 4.77 Impact Factor