Abstract
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 IFNγ/TNFα-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.
Highlights
Chronic non-communicable diseases including cardiometabolic, neurodegenerative, musculoskeletal, allergic, and autoimmune diseases are the major causes of human morbidity and mortality worldwide [1]
These results confirmed that the atheroprotective effect of our novel sc repetitive microdose delivery (REMID) strategy is not restricted to the Vitamin D3 (VitD)/Dexa formulation, and observed when using other IL-10/Treginducing hydrophobic small molecule such as curcumin
Based on a recent study from our group, in which we showed that low dose locally delivered VitD/Dexa was effective at halting the progress of atherosclerosis, via induction of IL-10-producing regulatory leukocytes instead of prompting direct systemic effects [30], here we hypothesized that other immunoregulatory small molecules administered on a similar sc REMID strategy should be able to restore the pro/antiinflammatory balance and impact disease
Summary
Chronic non-communicable diseases including cardiometabolic, neurodegenerative, musculoskeletal, allergic, and autoimmune diseases are the major causes of human morbidity and mortality worldwide [1]. Given the variety of organs and systems that could be affected, the management of chronic inflammatory diseases (CID) is complex and disease dependent. As a general rule, interventions are usually focused on mitigating or eliminating risk factors, improving the function of the affected organs, and reducing the inflammatory burden by using poorly specific immunosuppressive and/or anti-inflammatory drugs [3,4,5,6]. Advances in understanding of the immunopathological mechanisms underlying these diseases have identified proinflammatory mediators amenable for highly specific targeting with biological agents, such as anti-TNFa, anti-IL-6, or anti-IL-1b monoclonal antibodies (mAbs). Inflammatory responses are substantially impacted by these agents, immunosuppression and high financial costs
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