Potent Phagocytic Activity with Impaired Antigen Presentation Identifying Lipopolysaccharide-Tolerant Human Monocytes: Demonstration in Isolated Monocytes from Cystic Fibrosis Patients

Fresno, Carlos del; García‐Río, Francisco; Gómez-Piña, Vanesa; Soares‐Schanoski, Alessandra; Fernández-Ruíz, Irene; Jurado, Teresa; Kajiji, Tasneem; Shu, Chen; Marín, Elvira; Arroyo, Ana Gutierrez del; Prados, Concepción; Arnalich, Francisco; Fuentes‐Prior, Pablo; Biswas, Subrha K.; López-Collazo, Eduardo

doi:10.4049/jimmunol.0803350

Cited by 192 publications

(214 citation statements)

References 66 publications

(89 reference statements)

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“…Defective cytokine release in response to LPS, impaired antigen presenting function, and increased expression of anti-microbial genes are features reported for in vitro endotoxin tolerance (Biswas and Lopez-Collazo, 2009;del Fresno et al, 2009;Foster et al, 2007). Therefore, the present observations on SepsisMonocytes strongly suggest them to be conditioned to a refractory or endotoxin tolerant phenotype in vivo during sepsis.…”

Section: Monocytes Exhibit Hallmarks Of Endotoxin Tolerance In Vivo Imentioning

confidence: 57%

Human Monocytes Undergo Functional Re-programming during Sepsis Mediated by Hypoxia-Inducible Factor-1α

et al. 2015

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Sepsis is characterized by a dysregulated inflammatory response to infection. Despite studies in mice, the cellular and molecular basis of human sepsis remains unclear and effective therapies are lacking. Blood monocytes serve as the first line of host defense and are equipped to recognize and respond to infection by triggering an immune-inflammatory response. However, the response of these cells in human sepsis and their contribution to sepsis pathogenesis is poorly understood. To investigate this, we performed a transcriptomic, functional, and mechanistic analysis of blood monocytes from patients during sepsis and after recovery. Our results revealed the functional plasticity of monocytes during human sepsis, wherein they transited from a pro-inflammatory to an immunosuppressive phenotype, while enhancing protective functions like phagocytosis, anti-microbial activity, and tissue remodeling. Mechanistically, hypoxia inducible factor-1α (HIF1α) mediated this functional re-programming of monocytes, revealing a potential mechanism for their therapeutic targeting to regulate human sepsis.

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Section: Monocytes Exhibit Hallmarks Of Endotoxin Tolerance In Vivo Imentioning

confidence: 57%

Human Monocytes Undergo Functional Re-programming during Sepsis Mediated by Hypoxia-Inducible Factor-1α

et al. 2015

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“…It has been shown that monocytes from CF patients, when challenged with LPS, exhibit a tolerant IL-12 low IL-23 low IL-10 high phenotype with low antigen presentation capacity, which is indicative of an M2 polarization state [78]. In opposite, in the nasal tissue of CF patients we observed accumulation of CD14 ?…”

Section: Cystic Fibrosismentioning

confidence: 80%

Impairment of phagocytosis of apoptotic cells and its role in chronic airway diseases

et al. 2010

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Phagocytosis of dying cells is a complex and dynamic process coordinated by the interaction of many surface molecules, adaptors, and chemotactic molecules, and it is controlled at multiple levels. This well regulated clearance process is of utmost importance for the development and homeostasis of organisms because defective or inefficient phagocytosis may contribute to human pathologies. In this review we discuss recent advances in the knowledge of the molecular interactions involved in recognition and clearance of apoptotic cells and how derangement of these processes can contribute to the pathogenesis of chronic airway diseases such as chronic obstructive pulmonary disease, cystic fibrosis and asthma. We will briefly consider how different types of macrophages are implicated in chronic airway diseases. Finally, we will address possible therapeutic strategies, such as the use of macrolide antibiotics and statins, for modulating apoptotic cell clearance.

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“…Previous studies reported that the functions of several types of immune cells were modified via TLR4-dependent stimulation (30,(36)(37)(38). We were unable to ascertain whether the clinical efficacy of UT12 was due to its effect on neutrophils alone or resulted from its action on multiple immune response systems.…”

Section: Figmentioning

confidence: 68%

Toll-Like Receptor 4 Agonistic Antibody Promotes Host Defense against Chronic Pseudomonas aeruginosa Lung Infection in Mice

Nakamura

Iwanaga

Seki³

et al. 2016

Infect Immun

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f Chronic lower respiratory tract infection with Pseudomonas aeruginosa is difficult to treat due to enhanced antibiotic resistance and decreased efficacy of drug delivery to destroyed lung tissue. To determine the potential for restorative immunomodulation therapies, we evaluated the effect of Toll-like receptor 4 (TLR4) stimulation on the host immune response to Pseudomonas infection in mice. We implanted sterile plastic tubes precoated with P. aeruginosa in the bronchi of mice, administered the TLR4/ MD2 agonistic monoclonal antibody UT12 intraperitoneally every week, and subsequently analyzed the numbers of viable bacteria and inflammatory cells and the levels of cytokines. We also performed flow cytometry-based phagocytosis and opsonophagocytic killing assays in vitro using UT12-treated murine peritoneal neutrophils. UT12-treated mice showed significantly enhanced bacterial clearance, increased numbers of Ly6G ؉ neutrophils, and increased concentrations of macrophage inflammatory protein 2 (MIP-2) in the lungs (P < 0.05). Depletion of CD4 ؉ T cells eliminated the ability of the UT12 treatment to improve bacterial clearance and promote neutrophil recruitment and MIP-2 production. Additionally, UT12-pretreated peritoneal neutrophils exhibited increased opsonophagocytic killing activity via activation of the serine protease pathway, specifically neutrophil elastase activity, in a TLR4-dependent manner. These data indicated that UT12 administration significantly augmented the innate immune response against chronic bacterial infection, in part by promoting neutrophil recruitment and bactericidal function. Pseudomonas aeruginosa is extremely difficult to eradicate once established in the lower respiratory tract (LRT) during chronic respiratory infection. Poor penetration of antibiotics into purulent airway secretions due to lung structure damage, acquired antibiotic resistance, defects in mucosal defenses, and the interference of bacterium-produced biofilms with phagocytic killing impede treatment (1). Chronic P. aeruginosa infection also represents an independent risk factor for accelerated loss of pulmonary function and decreased survival (2, 3).Lipopolysaccharide (LPS) is a glycolipid component of the Gram-negative bacterial cell wall that is recognized by Toll-like receptor 4 (TLR4), which induces various host responses, including proinflammatory cytokine production, and has known immunomodulatory properties (4). Priming with LPS has been shown to improve murine responses to bacterial infections (5-7), and prior LPS exposure attenuates proinflammatory cytokine production in response to LPS or bacterial challenge, a phenomenon that has historically been referred to as endotoxin tolerance (8, 9). Several immunomodulators, such as the TLR4 agonist monophosphoryl lipid A (MPLA), promote host immunity and are used as vaccine adjuvants for humans (10). In animal models, MPLA enhances the action of macrophages, B cells, and other antigenpresenting cells and promotes the differentiation of Th1 and Th2 cells from naïv...

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Potent Phagocytic Activity with Impaired Antigen Presentation Identifying Lipopolysaccharide-Tolerant Human Monocytes: Demonstration in Isolated Monocytes from Cystic Fibrosis Patients

Cited by 192 publications

References 66 publications

Human Monocytes Undergo Functional Re-programming during Sepsis Mediated by Hypoxia-Inducible Factor-1α

Human Monocytes Undergo Functional Re-programming during Sepsis Mediated by Hypoxia-Inducible Factor-1α

Impairment of phagocytosis of apoptotic cells and its role in chronic airway diseases

Toll-Like Receptor 4 Agonistic Antibody Promotes Host Defense against Chronic Pseudomonas aeruginosa Lung Infection in Mice

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