Autonomous TNF is critical for in vivo monocyte survival in steady state and inflammation.
Monocytes are circulating mononuclear phagocytes, poised to extravasate to sites of inflammation and differentiate into monocyte-derived macrophages and dendritic cells. Tumor necrosis factor (TNF) and its receptors are up-regulated during monopoiesis and expressed by circulating monocytes, as well as effector monocytes infiltrating certain sites of inflammation, such as the spinal cord, during experimental autoimmune encephalomyelitis (EAE). In this study, using competitive in vitro and in vivo assays, we show that monocytes deficient forTNForTNFreceptors are outcompeted by their wild-type counterpart. Moreover, monocyte-autonomous TNF is critical for the function of these cells, asTNFablation in monocytes/macrophages, but not in microglia, delayed the onset of EAE in challenged animals and was associated with reduced acute spinal cord infiltration of Ly6Chieffector monocytes. Collectively, our data reveal a previously unappreciated critical cell-autonomous role ofTNFon monocytes for their survival, maintenance, and function.
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Yochai
Y
Wolf
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Anat
A
Shemer
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Michal
M
Polonsky
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Mor
M
Gross
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Alexander
A
Mildner
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Simon
0000-0002-3984-2008
S
Yona
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Eyal
E
David
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Ki-Wook
0000-0002-7207-4389
KW
Kim
Institute for Neuropathology, University of Freiburg, 79085 Freiburg, Germany.
Tobias
0000-0001-9754-9144
T
Goldmann
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Ido
I
Amit
Institut für Virologie, Helmholtz Zentrum München, 85764 Neuherberg, Germany.|Department of Chronic Inflammation and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany.
Mathias
M
Heikenwalder
Engelhardt Institute of Molecular Biology, Moscow, Russia 119991.|German Rheumatism Research Center, 10117 Berlin, Germany.
Sergei
S
Nedospasov
Institute for Neuropathology, University of Freiburg, 79085 Freiburg, Germany.|BIOSS Centre for Biological Signaling Studies, University of Freiburg, 79085 Freiburg, Germany.
Marco
M
Prinz
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Nir
N
Friedman
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel s.jung@weizmann.ac.il.
Steffen
0000-0003-4290-5716
S
Jung
D000818:Animals; D002470:Cell Survival; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000502:physiology; D009000:Monocytes / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha