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Potent Phagocytic Activity with Impaired Antigen Presentation Identifying Lipopolysaccharide-Tolerant Human Monocytes: Demonstration in Isolated Monocytes from Cystic Fibrosis Patients¹

Carlos del Fresno^*, Francisco García-Rio, Vanesa Gómez-Piña^*, Alessandra Soares-Schanoski^*, Irene Fernández-Ruíz^*, Teresa Jurado^*, Tasneem Kajiji, Chen Shu, Elvira Marín, Ana Gutierrez del Arroyo^¶, Concepción Prados, Francisco Arnalich^||, Pablo Fuentes-Prior^#, Subrha K. Biswas and Eduardo López-Collazo^2,*

^* Research Unit, Laboratory of Tumor Immunology, and Service of Respiratory Diseases, "La Paz" Hospital, Madrid, Spain; Singapore Immunology Network, Biomedical Sciences Institutes, Singapore; Discovery Unit, EMPIREO Diagnostic, Madrid, Spain; ^¶ Department of Medicine and Wolfson Institute for Biomedical Research, University College London, London, United Kingdom; ^|| Emergency Service, "La Paz" Hospital, "La Paz" Hospital Medical School, Universidad Autónoma de Madrid, Madrid, Spain; and ^# Cardiovascular Research Center and Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Monocyte exposure to LPS induces a transient state in which these cells are refractory to further endotoxin stimulation. This phenomenon, termed endotoxin tolerance (ET), is characterized by a decreased production of cytokines in response to the proinflammatory stimulus. We have established a robust model of ET and have determined the time frame and features of LPS unresponsiveness in cultured human monocytes. A large number of genes transcribed in tolerant monocytes were classified as either "tolerizable" or "nontolerizable" depending on their expression levels during the ET phase. Tolerant monocytes exhibit rapid IL-1R-associated kinase-M (IRAK-M) overexpression, high levels of triggering receptor expressed on myeloid cells-1 (TREM-1) and CD64, and a marked down-regulation of MHC molecules and NF-B2. These cells combine potent phagocytic activity with impaired capability for Ag presentation. We also show that circulating monocytes isolated from cystic fibrosis patients share all the determinants that characterize cells locked in an ET state. These findings identify a new mechanism that contributes to impaired inflammation in cystic fibrosis patients despite a high frequency of infections. Our results indicate that a tolerant phenotype interferes with timing, efficiency, and outcome of the innate immune responses against bacterial infections.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from "Ministerio de Ciencia e Innovación" (SAF1256 and SAF3290), Fondo Sanitarios de Investigación, and from "Fundación Médica de la Mutua Madrileña de Automovilística" (to E.L.-C.).

² Address correspondence and reprint requests to Dr. Eduardo López-Collazo, Research Unit, Laboratory of Tumor Immunology, "La Paz" Hospital, 28046 Madrid, Spain. E-mail address: elopezc.hulp{at}salud.madrid.org

³ Abbreviations used in this paper: ET, endotoxin tolerance; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; IRAK, IL-1R-associated kinase; , untreated cells; Q-PCR, quantitative PCR; TREM, triggering receptor expressed on myeloid cells; t_tol, time of tolerization; t_rec, time of recovery; t_st, time of stimulation.

⁴ The online version of this article contains supplemental material.

This article has been cited by other articles:

				O. Krysko, T. Van Zele, S. Claeys, and C. Bachert Comment on "Potent Phagocytic Activity with Impaired Antigen Presentation Identifying Lipopolysaccharide-Tolerant Human Monocytes: Demonstration in Isolated Monocytes from Cystic Fibrosis Patients" J. Immunol., October 15, 2009; 183(8): 4831 - 4832. [Full Text] [PDF]

				F. Garcia-Rio, C. del Fresno, P. Fuentes-Prior, and E. Lopez-Collazo Response to Comment on "Potent Phagocytic Activity with Impaired Antigen Presentation Identifying Lipopolysaccharide-Tolerant Human Monocytes: Demonstration in Isolated Monocytes from Cystic Fibrosis Patients" J. Immunol., October 15, 2009; 183(8): 4831 - 4832. [Full Text] [PDF]