On a Western diet, APOE ɛ4 is associated with low innate immune sensing, but not APOE ɛ3

Abstract

IL-2 ''virtual'' injections every 3 days, Treg cells were expected to remain stable with a delta variation of %Treg cells ranging from 3 to 4 (ie, a 60%-80% increase); with 3 MIU every 3 days, %Treg cells were predicted to increase continuously; with reinjections every 15 days, Treg cells were expected to (1) return to their baseline approximately at day 20 with 0.33 MIU; (2) be stable with a delta variation of %Treg cells ranging from 0.5 to 1.5 (ie, 10%-30% increase) with 1 MIU; and (3) to be stable with a delta variation of % of Treg cells ranging from 2.5 to 3.5 (ie, 50%-70% increase) using 3 MIU.On the basis of safety data from our previous clinical trials and our modeling, we chose the dose of 1 MIU/injection, with once-a-fortnight injections during the maintenance course to perform a novel clinical trial of ld-IL2 in patients with mild forms of various AIDs (rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet disease, Wegener granulomatosis, Takayasu disease, Crohn disease, ulcerative colitis, autoimmune hepatitis, sclerosing cholangitis, and Gougerot-Sj€ ogren syndrome; Transreg clinical trial: NCT01988506). Treg-cell dynamics over time in the first 40 treated patients is presented in Fig 2 , B. Note that Treg-cell evaluations were always made just before an IL-2 injection, thus 14 days away from the last injection. These values therefore underestimate the overall effect during the 14-day period. As predicted from above, %Treg cells was increased during the maintenance phase in treated patients (delta of 1.12% 6 0.25%, P < .0001 at day 31, and 1.325% 6 0.33%, P < .0001 at day 91), representing a minimum 20% increase for a prediction that was between 10% and 30%.Thus, we have defined and validated a model for predicting the dynamic Treg-cell response to IL-2 that should help navigate its use in numerous therapeutic targets, from various AIDs to transplantation and allergy. Our pharmacodynamic model can predict the effects of any combination of any of the treatment parameters: dose, length of the induction phase, timing of maintenance injections. Also, our results show that the response to IL-2 is predictable across multiple AIDs and that we have validated a therapeutic scheme that provides long-term improvement in the Teff-/Treg-cell balance.We are grateful to Alice Barrateau for excellent technical assistance. We thank the animal care team members Christelle Enond, Bocar Kane, Olivier Bregerie, and Serban Morosan from the Centre d'Exploration Fonctionnelle, UPMC Paris 06. We thank the entire DF-IL2 and Transreg study groups for the performance of the clinical trials that contributed to this study (groups are listed in this article's Online Repository at www.jacionline.org).

High-fat diet increases gliosis and immediate early gene expression in APOE3 mice, but not APOE4 mice

“…Another study showed HFD caused a decrease in CD68 (a marker of monocyte-derived cells) in APOE 4 mice [ 17 ]. While data support that APOE 4 mice have an increased response to short-term noxious stimuli such as LPS treatment or injury [ 23 , 52 , 57 ], there is evidence of a decreased response to the chronic inflammation caused by obesity [ 8 , 17 ]. In one study, APOE 3 and APOE 4 mice were fed a HFD for approximately 7 months, and there were APOE 3 -specific increases in expression of TNFα, IL-6, and CD36 when compared to APOE 4 mice [ 8 ].…”

“…While data support that APOE 4 mice have an increased response to short-term noxious stimuli such as LPS treatment or injury [ 23 , 52 , 57 ], there is evidence of a decreased response to the chronic inflammation caused by obesity [ 8 , 17 ]. In one study, APOE 3 and APOE 4 mice were fed a HFD for approximately 7 months, and there were APOE 3 -specific increases in expression of TNFα, IL-6, and CD36 when compared to APOE 4 mice [ 8 ]. APOE 4 mice also exhibited lower expression of LPS immune sensors indicating a decreased ability for innate immune detection [ 8 ].…”

APOE4is associated with elevated blood lipids and lower levels of innate immune biomarkers in a tropical Amerindian subsistence population

“…Other studies have documented lower baseline levels of certain proinflammatory cytokines (e.g. IL-6, TNF-alpha) in APOE4+ carriers (Olgiati et al, 2010), and downregulated expression of biomarkers mediating innate immune sensing (TLR-signaling molecules) (Dose et al, 2018). Experimental studies also showed the associations of APOE4 with heightened innate and complement inflammatory responses to lipopolysaccharide (LPS) stimulation in (Gale et al, 2014;Tzioras et al, 2019).…”

“…APOE4+ carriers consistently show higher levels of total cholesterol, low-density lipoprotein (LDL), and oxidized-LDL (Safieh et al, 2019, Yassine and. While some studies suggest APOE4+ carriers have higher inflammatory responses (Gale et al, 2014;Olgiati et al, 2010), the APOE4 allele is also associated with downregulation of aspects of innate immune function at baseline, including acute-phase proteins (Lumsden et al, 2020;Martiskainen et al, 2018;Vasunilashorn et al, 2011), and toll-like receptor (TLR) signaling molecules (Dose et al, 2018). APOE, lipids, and immune function may interact differently in contemporary obesogenic post-industrial contexts compared to environments where infections are prevalent.…”

“…Other studies have documented lower baseline levels of certain proinflammatory cytokines (e.g. IL-6, TNF-alpha) in APOE4+ carriers (Olgiati et al, 2010), and downregulated expression of biomarkers mediating innate immune sensing (TLR-signaling molecules) (Dose et al, 2018).…”