Reformulating Small Molecules for Cardiovascular Disease Immune Intervention: Low-Dose Combined Vitamin D/Dexamethasone Promotes IL-10 Production and Atheroprotection in Dyslipidemic Mice

Abstract

Ospina-Quintero et al. Regulatory Cell-Inducing Small Molecule Formulation non-immunosuppressive, low-dose of VitD/Dexa, administered subcutaneously and repetitively, exerts atheroprotective effects in dyslipidemic mice, apparently due to the induction of an IL-10-producing network of lymphoid and myeloid immune cells. These well known, widely available, and inexpensive small molecules can be easily coformulated into a simple and accessible agent with a potential use as a prophylactic or therapeutic immune intervention for CVD and other chronic inflammatory diseases.

IL-10-Dependent Amelioration of Chronic Inflammatory Disease by Microdose Subcutaneous Delivery of a Prototypic Immunoregulatory Small Molecule

“…Collectively, the results presented here, together with our previous study (30), propose a novel and more rational approach to promote the restoration of the pro/anti-inflammatory balance, by exploiting the immunoregulatory properties of curcumin and other IL-10-inducing small molecules and bypassing the high dose and systemic exposure requirements. In our strategy, endogenous IL-10 is induced via microdose local delivery of hydrophobic small molecules such as curcumin, VitD or Dexa, avoiding the inconveniences of systemic drugs or exogenous IL-10 supplementation.…”

“…Spleens, livers, and kidneys were weighted and counts of total and viable splenocytes were obtained by trypan blue exclusion. Cryosections from the aortic root were used to quantify atherosclerotic lesion size and lipid deposition area by H&E and Oil red O-staining, respectively, as previously reported ( 30 ). Immunofluorescence microscopy analysis was also performed to evaluate inflammatory infiltrates of macrophages and T cells in the aortic sinus by using anti-CD68 and anti-CD3 mAb, as reported ( 31 ).…”

“…In a previous proof of concept report, we proposed a novel immunomodulatory strategy consisting in the local low-dose delivery of an IL-10-inducing formulation (containing VitD/ Dexa) as a form of immune intervention for atherosclerosis (30). Since other hydrophobic small molecules have similar tolDC/ Treg-inducing properties (23)(24)(25)(26)(38)(39)(40), we postulated that after a similar dose and form of administration of any of them, an atheroprotective effect should be reproduced.…”

“…A number of synthetic and natural small molecules (such as dexamethasone, Dexa, and vitamin D, VitD) have been reported to act as IL-10 inducers in vitro and in vivo (23)(24)(25)(26)(27), and investigations that explore different formulations, delivery systems, and route/dose/scheme of administration could be of particular interest to develop realistic forms of immune interventions for CID. Based on the synergistic activity of VitD and Dexa to induce IL-10 and promote Tregs (28,29), we recently postulated and demonstrated that a subcutaneous (sc) repetitive microdose delivery (REMID) strategy of a combined VitD/Dexa formulation increased the number of IL-10-producing leukocytes, reduced the Th1 proinflammatory response and attenuated the progression of atherosclerotic lesions (30), the major underlying cause of cardiovascular disease (CVD). These results constitute the preclinical proof of concept for a simple inexpensive hydrophobic small molecule-based formulation that can be repurposed to promote IL-10-producing cells in vivo and, therefore, as a potential safe, effective, and realistic form of immune intervention (30).…”

“…Based on the synergistic activity of VitD and Dexa to induce IL-10 and promote Tregs ( 28 , 29 ), we recently postulated and demonstrated that a subcutaneous (sc) repetitive microdose delivery (REMID) strategy of a combined VitD/Dexa formulation increased the number of IL-10-producing leukocytes, reduced the Th1 proinflammatory response and attenuated the progression of atherosclerotic lesions ( 30 ), the major underlying cause of cardiovascular disease (CVD). These results constitute the preclinical proof of concept for a simple inexpensive hydrophobic small molecule-based formulation that can be repurposed to promote IL-10-producing cells in vivo and, therefore, as a potential safe, effective, and realistic form of immune intervention ( 30 ). In this study, we tested the hypothesis that a similar form of delivery of other IL-10-inducing immunoregulatory small molecule, such as curcumin, ameliorates chronic inflammation in two CID mouse models (atherosclerosis and experimental autoimmune encephalomyelitis, EAE) via immune system regulation.…”