title: The Tetraspanin TSPAN33 Controls TLR-Triggered Macrophage Activation through Modulation of NOTCH Signaling.
abstract: The involvement of NOTCH signaling in macrophage activation by Toll receptors has been clearly established, but the factors and pathways controlling NOTCH signaling during this process have not been completely delineated yet. We have characterized the role of TSPAN33, a tetraspanin implicated in a disintegrin and metalloproteinase (ADAM) 10 maturation, during macrophage proinflammatory activation. Tspan33 expression increases in response to TLR signaling, including responses triggered by TLR4, TLR3, and TLR2 activation, and it is enhanced by IFN-γ. In this study, we report that induction of Tspan33 expression by TLR and IFN-γ is largely dependent on NOTCH signaling, as its expression is clearly diminished in macrophages lacking Notch1 and Notch2 expression, but it is enhanced after overexpression of a constitutively active intracellular domain of NOTCH1. TSPAN33 is the member of the TspanC8 tetraspanin subgroup more intensely induced during macrophage activation, and its overexpression increases ADAM10, but not ADAM17, maturation. TSPAN33 favors NOTCH processing at the membrane by modulating ADAM10 and/or Presenilin1 activity, thus increasing NOTCH signaling in activated macrophages. Moreover, TSPAN33 modulates TLR-induced proinflammatory gene expression, at least in part, by increasing NF-κB-dependent transcriptional activity. Our results suggest that TSPAN33 represents a new control element in the development of inflammation by macrophages that could constitute a potential therapeutic target.
authors: Facultad de Medicina, Centro Regional de Investigaciones Biomédicas, Unidad de Biomedicina, Universidad de Castilla-La Mancha/Consejo Superior de Investigaciones Cientificas, 02006 Albacete, Spain.
authors: Almudena
authors: A
authors: Ruiz-García
authors: Facultad de Medicina, Centro Regional de Investigaciones Biomédicas, Unidad de Biomedicina, Universidad de Castilla-La Mancha/Consejo Superior de Investigaciones Cientificas, 02006 Albacete, Spain.
authors: Susana
authors: S
authors: López-López
authors: Facultad de Medicina, Centro Regional de Investigaciones Biomédicas, Unidad de Biomedicina, Universidad de Castilla-La Mancha/Consejo Superior de Investigaciones Cientificas, 02006 Albacete, Spain.
authors: José Javier
authors: 0000-0002-8348-3727
authors: JJ
authors: García-Ramírez
authors: Facultad de Medicina, Centro Regional de Investigaciones Biomédicas, Unidad de Biomedicina, Universidad de Castilla-La Mancha/Consejo Superior de Investigaciones Cientificas, 02006 Albacete, Spain.
authors: Victoriano
authors: V
authors: Baladrón
authors: Facultad de Medicina, Centro Regional de Investigaciones Biomédicas, Unidad de Biomedicina, Universidad de Castilla-La Mancha/Consejo Superior de Investigaciones Cientificas, 02006 Albacete, Spain.
authors: María José
authors: 0000-0003-2508-8398
authors: MJ
authors: Ruiz-Hidalgo
authors: Facultad de Medicina, Centro Regional de Investigaciones Biomédicas, Unidad de Biomedicina, Universidad de Castilla-La Mancha/Consejo Superior de Investigaciones Cientificas, 02006 Albacete, Spain.
authors: Laura
authors: L
authors: López-Sanz
authors: Facultad de Medicina, Centro Regional de Investigaciones Biomédicas, Unidad de Biomedicina, Universidad de Castilla-La Mancha/Consejo Superior de Investigaciones Cientificas, 02006 Albacete, Spain.
authors: Ángela
authors: Á
authors: Ballesteros
authors: Facultad de Medicina, Centro Regional de Investigaciones Biomédicas, Unidad de Biomedicina, Universidad de Castilla-La Mancha/Consejo Superior de Investigaciones Cientificas, 02006 Albacete, Spain.
authors: Jorge
authors: 0000-0002-9210-838X
authors: J
authors: Laborda
authors: Facultad de Medicina, Centro Regional de Investigaciones Biomédicas, Unidad de Biomedicina, Universidad de Castilla-La Mancha/Consejo Superior de Investigaciones Cientificas, 02006 Albacete, Spain mariajose.martinez@uclm.es evamaria.monsalve@uclm.es.
authors: Eva María
authors: 0000-0003-4933-4602
authors: EM
authors: Monsalve
authors: Facultad de Medicina, Centro Regional de Investigaciones Biomédicas, Unidad de Biomedicina, Universidad de Castilla-La Mancha/Consejo Superior de Investigaciones Cientificas, 02006 Albacete, Spain mariajose.martinez@uclm.es evamaria.monsalve@uclm.es.
authors: María José M
authors: 0000-0003-3843-3912
authors: MJ
authors: Díaz-Guerra
mesh_terms: D000818:Animals; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000067996:RAW 264.7 Cells; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D059470:Tetraspanins / Q000235:genetics / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D051880:Receptors, Notch; C505521:TSPAN33 protein, human; D059470:Tetraspanins; D051193:Toll-Like Receptors