Prodigiosin Modulates the Immune Response and Could Promote a Stable Atherosclerotic Lession in C57bl/6 Ldlr-/- Mice

Abstract

Atherosclerosis is a chronic inflammatory disease, whose progression and stability are modulated, among other factors, by an innate and adaptive immune response. Prodiginines are bacterial secondary metabolites with antiproliferative and immunomodulatory activities; however, their effect on the progression or vulnerability of atheromatous plaque has not been evaluated. This study assessed the therapeutic potential of prodigiosin and undecylprodigiosin on inflammatory marker expression and atherosclerosis. An in vitro and in vivo study was carried out. Migration, low-density lipoprotein (LDL) uptake and angiogenesis assays were performed on cell types involved in the pathophysiology of atherosclerosis. In addition, male LDL receptor null (Ldlr-/-) C57BL/6J mice were treated with prodigiosin or undecylprodigiosin for 28 days. Morphometric analysis of atherosclerotic plaques, gene expression of atherogenic factors in the aortic sinus and serum cytokine quantification were performed. The treatments applied had slight effects on the in vitro tests performed, highlighting the inhibitory effect on the migration of SMCs (smooth muscle cells). On the other hand, although no significant difference in atherosclerotic plaque progression was observed, gene expression of IL-4 and chemokine (C-C motif) ligand 2 (Ccl2) was downregulated. In addition, 50 µg/Kg/day of both treatments was sufficient to inhibit circulating tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2) and interferon-gamma (IFN-γ) in serum. These results suggested that prodigiosin and undecylprodigiosin modulated inflammatory markers and could have an impact in reducing atherosclerotic plaque vulnerability.

Rise of the natural red pigment ‘prodigiosin’ as an immunomodulator in cancer

“…Cuevas et al ., recently showed that prodigiosin modulated the immune response and stabilised atherosclerotic lesions by inhibiting circulating TNF-α, IL-2, and IFN-γ in vivo (Fig. 3 ) [ 158 ]. Activation of M1 macrophages via IFN-γ is essential in immune function and contributes to tissue damage by proinflammatory cytokines [ 136 ].…”

Bioengineering of Anti‐Inflammatory Natural Products

“…Various studies showed that the prodiginines delay the progression of arthritis and improve gastric inflammations by interference with inflammatory mediators, such as the IL-2 receptor α-chain, NFkB, nitric oxide (NO), iNOS or JNK. [59][60][61][62][63] In silico studies further suggest that the prodiginines act as COX-2 inhibitors. [64] Because the total syntheses of prodiginines are costly and typically involve several steps with an overall low yield, [65,66] alternative manufacturing ways have been sought.…”