Activation of autophagy in macrophages by pro-resolving lipid mediators.
The resolution of inflammation is an active process driven by specialized pro-resolving lipid mediators, such as 15-epi-LXA4 and resolvin D1 (RvD1), that promote tissue regeneration. Macrophages regulate the innate immune response being key players during the resolution phase to avoid chronic inflammatory pathologies. Their half-life is tightly regulated to accomplish its phagocytic function, allowing the complete cleaning of the affected area. The balance between apoptosis and autophagy appears to be essential to control the survival of these immune cells within the inflammatory context. In the present work, we demonstrate that 15-epi-LXA4 and RvD1 at nanomolar concentrations promote autophagy in murine and human macrophages. Both compounds induced the MAP1LC3-I to MAP1LC3-II processing and the degradation of SQSTM1 as well as the formation of MAP1LC3(+) autophagosomes, a typical signature of autophagy. Furthermore, 15-epi-LXA4 and RvD1 treatment favored the fusion of the autophagosomes with lysosomes, allowing the final processing of the autophagic vesicles. This autophagic response involves the activation of MAPK1 and NFE2L2 pathways, but by an MTOR-independent mechanism. Moreover, these pro-resolving lipids improved the phagocytic activity of macrophages via NFE2L2. Therefore, 15-epi-LXA4 and RvD1 improved both survival and functionality of macrophages, which likely supports the recovery of tissue homeostasis and avoiding chronic inflammatory diseases.
a Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM) ; Madrid , Spain.
Patricia
P
Prieto
a Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM) ; Madrid , Spain.|b Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina; Universidad Autónoma de Nuevo León; Francisco I Madero y Eduardo Aguirre Pequeño S/N, Colonia Mitras Centro ; Monterrey , Nuevo León , México.
César Eduardo
CE
Rosales-Mendoza
a Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM) ; Madrid , Spain.
Verónica
V
Terrón
c Instituto de Investigación Hospital Universitario La Paz (IdiPAZ) ; Madrid , Spain.
Víctor
V
Toledano
a Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM) ; Madrid , Spain.|c Instituto de Investigación Hospital Universitario La Paz (IdiPAZ) ; Madrid , Spain.
Antonio
A
Cuadrado
c Instituto de Investigación Hospital Universitario La Paz (IdiPAZ) ; Madrid , Spain.
Eduardo
E
López-Collazo
a Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM) ; Madrid , Spain.
Gerard
G
Bannenberg
a Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM) ; Madrid , Spain.
Paloma
P
Martín-Sanz
c Instituto de Investigación Hospital Universitario La Paz (IdiPAZ) ; Madrid , Spain.
María
M
Fernández-Velasco
a Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM) ; Madrid , Spain.
Lisardo
L
Boscá
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D006207:Half-Life; D007249:Inflammation / Q000378:metabolism*; D044045:Lipoxins / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D016207:Cytokines; D044045:Lipoxins; C040527:lipoxin A4; C518399:resolvin D1; D004281:Docosahexaenoic Acids
15-epi-lipoxin-A4; inflammation; macrophages resolution; resolvin-D1