Lipopolysaccharide-Elicited TSLPR Expression Enriches a Functionally Discrete Subset of Human CD14+CD1c+Monocytes.
Thymic stromal lymphopoietin (TSLP) is a cytokine produced mainly by epithelial cells in response to inflammatory or microbial stimuli and binds to the TSLP receptor (TSLPR) complex, a heterodimer composed of TSLPR and IL-7 receptor α (CD127). TSLP activates multiple immune cell subsets expressing the TSLPR complex and plays a role in several models of disease. Although human monocytes expressTSLPRandCD127mRNAs in response to the TLR4 agonist LPS, their responsiveness to TSLP is poorly defined. We demonstrate that TSLP enhances human CD14+monocyte CCL17 production in response to LPS and IL-4. Surprisingly, only a subset of CD14+CD16-monocytes, TSLPR+monocytes (TSLPR+mono), expresses TSLPR complex upon LPS stimulation in an NF-κB- and p38-dependent manner. Phenotypic, functional, and transcriptomic analysis revealed specific features of TSLPR+mono, including higher CCL17 and IL-10 production and increased expression of genes with important immune functions (i.e.,GAS6,ALOX15B,FCGR2B,LAIR1). Strikingly, TSLPR+mono express higher levels of the dendritic cell marker CD1c. This evidence led us to identify a subset of peripheral blood CD14+CD1c+cells that expresses the highest levels of TSLPR upon LPS stimulation. The translational relevance of these findings is highlighted by the higher expression ofTSLPRandCD127mRNAs in monocytes isolated from patients with Gram-negative sepsis compared with healthy control subjects. Our results emphasize a phenotypic and functional heterogeneity in an apparently homogeneous population of human CD14+CD16-monocytes and prompt further ontogenetic and functional analysis of CD14+CD1c+and LPS-activated CD14+CD1c+TSLPR+mono.
Department of Translational Medical Sciences, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.|Center for Basic and Clinical Immunology Research, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.
Francesco
0000-0001-9074-4828
F
Borriello
Department of Translational Medical Sciences, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.|Center for Basic and Clinical Immunology Research, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.
Raffaella
0000-0003-2869-6719
R
Iannone
Department of Translational Medical Sciences, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.
Sarah
S
Di Somma
Department of Translational Medical Sciences, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.
Viviana
0000-0002-5156-7846
V
Vastolo
BioMed X Innovation Center, 69120 Heidelberg, Germany.
Giuseppe
0000-0002-2835-4308
G
Petrosino
CEINGE-Biotecnologie Avanzate, Università di Napoli Federico II, 80131 Naples, Italy.
Feliciano
0000-0002-4212-9385
F
Visconte
CEINGE-Biotecnologie Avanzate, Università di Napoli Federico II, 80131 Naples, Italy.
Maddalena
M
Raia
CEINGE-Biotecnologie Avanzate, Università di Napoli Federico II, 80131 Naples, Italy.
Giulia
G
Scalia
Department of Translational Medical Sciences, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.|Center for Basic and Clinical Immunology Research, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.
Stefania
S
Loffredo
Department of Translational Medical Sciences, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.|Center for Basic and Clinical Immunology Research, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.
Gilda
0000-0002-9285-4657
G
Varricchi
Department of Translational Medical Sciences, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.|Center for Basic and Clinical Immunology Research, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.
Maria Rosaria
0000-0002-8086-9130
MR
Galdiero
Department of Translational Medical Sciences, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.|Center for Basic and Clinical Immunology Research, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.
Francescopaolo
0000-0002-2793-8889
F
Granata
CEINGE-Biotecnologie Avanzate, Università di Napoli Federico II, 80131 Naples, Italy.|Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy; and.
Luigi
L
Del Vecchio
Department of Translational Medical Sciences, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.
Giuseppe
0000-0001-8276-9769
G
Portella
Department of Translational Medical Sciences, School of Medicine, University of Naples Federico II, 80131 Naples, Italy; marone@unina.it.|Center for Basic and Clinical Immunology Research, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.|Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore," National Research Council, 80131 Naples, Italy.
Gianni
G
Marone
D018949:Antigens, CD1 / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D054414:Chemokine CCL17 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D016130:Immunophenotyping; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D015847:Interleukin-4 / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D009000:Monocytes / Q000276:immunology*; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics; D018805:Sepsis / Q000276:immunology*; D000094632:Thymic Stromal Lymphopoietin; D000099255:Growth Arrest-Specific Protein 6
D018949:Antigens, CD1; D001093:Arachidonate 15-Lipoxygenase; D054414:Chemokine CCL17; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D015847:Interleukin-4; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D018121:Receptors, Cytokine; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D000094632:Thymic Stromal Lymphopoietin; D000099255:Growth Arrest-Specific Protein 6; C498762:CRLF2 protein, human; C499173:FCGR2B protein, human; C108073:leukocyte-associated immunoglobulin-like receptor 1; C458528:ALOX15B protein, human