Control of inflammation by microglial HO-1 is differentially regulated with aging
C. Fernández-Mendívil1, E. Luengo1, P. Trigo-Alonso1, I. Buendia1,2 and M. G. Lopez1,2.
1Institute Teófilo Hernando, Madrid, Spain; 2 Hospital Universitario La Princesa. Madrid, Spain.
Neurodegenerative diseases share pathological mechanisms such as oxidative stress or chronic inflammation, processes in which microglial cells have a pivotal role. It has been proven that microglial heme-oxygenase 1 (HO-1) enzyme has anti-inflammatory, antioxidant and neuroprotective effects. However, in patients with Alzheimer's disease and during aging, the expression and activity of HO-1 is increased compared to adult and healthy subjects. Therefore, our aim was to understand the role of HO-1 under inflammatory conditions, both in adult and aged wild type (WT) mice and LysMCreHmox1△△ (KO HO-1) mice, which lack the HO-1 enzyme in microglial cells.
Initially, 3-month-old mice were treated with LPS and the results of behavioral parameters showed that the KO HO-1 animals presented a worse behavioral profile than the WT mice at 4 and 8 hours after the injection of the inflammatory stimulus. In addition, the absence of microglial HO-1 was related with a higher release of pro-inflammatory cytokines and with an increase in pro-oxidant enzymes. In addition, WT mice treated 2 hours before the injection of LPS with zinc protoporphyrin (ZnPP), as a pharmacological tool to inhibit the activity of total HO-1, provided similar results to the ones observed in KO HO-1 animals. To study the implications of the absence of HO-1 in the inflammatory response in aged animals, 15-months-old mice treated with ZnPP or KO HO-1 were used. The results of behavioral parameters and biochemical analysis showed that WT animals treated with ZnPP and KO HO-1 mice subjected to LPS presented a better anti-inflammatory response compared to their respective controls treated with LPS.
Taken all together, these results highlight the importance of microglial HO-1 in resolving inflammation with age; its absence in young animals is related to a higher inflammatory profile, while its absence in aged mice seems to be beneficial. Therefore, regulation of HO-1 to resolve the inflammatory state that underlies many NDDs is tightly dependent on age.
Funding. The Spanish MINECO (SAF2015-63936R) supported this work and it was possible thanks to the FPU scholarship granted by the Ministry of Education, Culture and Sports (FPU15/03269).