Browsing by Author "Retamal-Diaz, Angello"

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    IL-10-Dependent Amelioration of Chronic Inflammatory Disease by Microdose Subcutaneous Delivery of a Prototypic Immunoregulatory Small Molecule
    (2021) Tabares-Guevara, Jorge H.; Jaramillo, Julio C.; Ospina-Quintero, Laura; Piedrahita-Ochoa, Christian A.; Garcia-Valencia, Natalia; Bautista-Erazo, David E.; Caro-Gomez, Erika; Covian, Camila; Retamal-Diaz, Angello; Duarte, Luisa F.; Gonzalez, Pablo A.; Bueno, Susan M.; Riedel, Claudia A.; Kalergis, Alexis M.; Ramirez-Pineda, Jose R.
    One of the interventional strategies to reestablish the immune effector/regulatory balance, that is typically altered in chronic inflammatory diseases (CID), is the reinforcement of endogenous immunomodulatory pathways as the one triggered by interleukin (IL)-10. In a recent work, we demonstrated that the subcutaneous (sc) administration of an IL-10/Treg-inducing small molecule-based formulation, using a repetitive microdose (REMID) treatment strategy to preferentially direct the effects to the regional immune system, delays the progression of atherosclerosis. Here we investigated whether the same approach using other IL-10-inducing small molecule, such as the safe, inexpensive, and widely available polyphenol curcumin, could induce a similar protective effect in two different CID models. We found that, in apolipoprotein E deficient mice, sc treatment with curcumin following the REMID strategy induced atheroprotection that was not consequence of its direct systemic lipid-modifying or antioxidant activity, but instead paralleled immunomodulatory effects, such as reduced proatherogenic IFN gamma/TNF alpha-producing cells and increased atheroprotective FOXP3(+) Tregs and IL-10-producing dendritic and B cells. Remarkably, when a similar strategy was used in the neuroinflammatory model of experimental autoimmune encephalomyelitis (EAE), significant clinical and histopathological protective effects were evidenced, and these were related to an improved effector/regulatory cytokine balance in restimulated splenocytes. The essential role of curcumin-induced IL-10 for neuroprotection was confirmed by the complete abrogation of the clinical effects in IL-10-deficient mice. Finally, the translational therapeutic prospection of this strategy was evidenced by the neuroprotection observed in mice starting the treatment one week after disease triggering. Collectively, results demonstrate the power of a simple natural IL-10-inducing small molecule to tackle chronic inflammation, when its classical systemic and direct pharmacological view is shifted towards the targeting of regional immune cells, in order to rationally harness its immunopharmacological potential. This shift implies that many well-known IL-10-inducing small molecules could be easily reformulated and repurposed to develop safe, innovative, and accessible immune-based interventions for CID.
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    Pharmacological Inhibition of IRE-1 Alpha Activity in Herpes Simplex Virus Type 1 and Type 2-Infected Dendritic Cells Enhances T Cell Activation
    (2022) Tognarelli, Eduardo I.; Retamal-Diaz, Angello; Farias, Monica A.; Duarte, Luisa F.; Palomino, Tomas F.; Ibanez, Francisco J.; Riedel, Claudia A.; Kalergis, Alexis M.; Bueno, Susan M.; Gonzalez, Pablo A.
    Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections are life-long and highly prevalent in the human population. These viruses persist in the host, eliciting either symptomatic or asymptomatic infections that may occur sporadically or in a recurrent manner through viral reactivations. Clinical manifestations due to symptomatic infection may be mild such as orofacial lesions, but may also translate into more severe diseases, such as ocular infections that may lead to blindness and life-threatening encephalitis. A key feature of herpes simplex viruses (HSVs) is that they have evolved molecular determinants that hamper numerous components of the host's antiviral innate and adaptive immune system. Importantly, HSVs infect and negatively modulate the function of dendritic cells (DCs), by inhibiting their T cell-activating capacity and eliciting their apoptosis after infection. Previously, we reported that HSV-2 activates the splicing of the mRNA of XBP1, which is related to the activity of the unfolded protein response (UPR) factor Inositol-Requiring Enzyme 1 alpha (IRE-1 alpha). Here, we sought to evaluate if the activation of the IRE-1 alpha pathway in DCs upon HSV infection may be related to impaired DC function after infection with HSV-1 or HSV-2. Interestingly, the pharmacological inhibition of the endonuclease activity of IRE-1 alpha in HSV-1- and HSV-2-infected DCs significantly reduced apoptosis in these cells and enhanced their capacity to migrate to lymph nodes and activate virus-specific CD4(+) and CD8(+) T cells. These findings suggest that the activation of the IRE-1 alpha-dependent UPR pathway in HSV-infected DCs may play a significant role in the negative effects that these viruses exert over these cells and that the modulation of this signaling pathway may be relevant for enhancing the function of DCs upon infection with HSVs.