Tumor necrosis factor-α blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation

Moshe Sade-Feldman; Julia Kanterman; Eliran Ish-Shalom; Mazal Elnekave; Elad Horwitz; Michal Baniyash

doi:10.1016/j.immuni.2013.02.007

Tumor necrosis factor-α blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation

Immunity. 2013 Mar 21;38(3):541-54. doi: 10.1016/j.immuni.2013.02.007. Epub 2013 Mar 7.

Authors

Moshe Sade-Feldman¹, Julia Kanterman, Eliran Ish-Shalom, Mazal Elnekave, Elad Horwitz, Michal Baniyash

Affiliation

¹ The Lautenberg Center for General and Tumor Immunology, The Institute for Medical Research Israel-Canada.

PMID: 23477736
DOI: 10.1016/j.immuni.2013.02.007

Abstract

Elevated concentrations of tumor necrosis factor-α (TNF-α) are detected in pathologies characterized by chronic inflammation. Whether TNF-α plays a role in manipulating the host's immune system toward generating an immunosuppressive milieu, typical of ongoing chronic inflammation, is unclear. Here we showed that TNF-α exhibited a dual function during chronic inflammation: arresting differentiation of immature myeloid-derived suppressor cells (MDSCs) primarily via the S100A8 and S100A9 inflammatory proteins and their corresponding receptor (RAGE) and augmenting MDSC suppressive activity. These functions led to in vivo T and NK cell dysfunction accompanied by T cell antigen receptor ζ chain downregulation. Furthermore, administration of etanercept (TNF-α antagonist) during early chronic inflammatory stages reduced MDSCs' suppressive activity and enhanced their maturation into dendritic cells and macrophages, resulting in the restoration of in vivo immune functions and recovery of ζ chain expression. Thus, TNF has a fundamental role in promoting an immunosuppressive environment generated during chronic inflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Calgranulin A / genetics
Calgranulin A / immunology
Calgranulin A / metabolism
Calgranulin B / genetics
Calgranulin B / immunology
Calgranulin B / metabolism
Cell Differentiation / drug effects
Cell Differentiation / genetics
Cell Differentiation / immunology*
Cells, Cultured
Chronic Disease
Etanercept
Flow Cytometry
Gene Expression / immunology
Immunoblotting
Immunoglobulin G / pharmacology
Inflammation / genetics
Inflammation / immunology*
Inflammation / metabolism
Killer Cells, Natural / immunology
Killer Cells, Natural / metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Mitogen-Activated Protein Kinases / genetics
Mitogen-Activated Protein Kinases / immunology
Mitogen-Activated Protein Kinases / metabolism
Myeloid Cells / drug effects
Myeloid Cells / immunology*
Myeloid Cells / metabolism
Receptors, Antigen, T-Cell / genetics
Receptors, Antigen, T-Cell / immunology
Receptors, Antigen, T-Cell / metabolism
Receptors, Tumor Necrosis Factor
Reverse Transcriptase Polymerase Chain Reaction
T-Lymphocytes / immunology
T-Lymphocytes / metabolism
Tumor Necrosis Factor-alpha / antagonists & inhibitors
Tumor Necrosis Factor-alpha / genetics
Tumor Necrosis Factor-alpha / immunology*

Substances

Anti-Inflammatory Agents, Non-Steroidal
Calgranulin A
Calgranulin B
Immunoglobulin G
Receptors, Antigen, T-Cell
Receptors, Tumor Necrosis Factor
S100A9 protein, mouse
Tumor Necrosis Factor-alpha
Mok protein, mouse
Mitogen-Activated Protein Kinases
Etanercept