Block of the Mevalonate Pathway Triggers Oxidative and Inflammatory Molecular Mechanisms Modulated by Exogenous Isoprenoid Compounds

Abstract

Deregulation of the mevalonate pathway is known to be involved in a number of diseases that exhibit a systemic inflammatory phenotype and often neurological involvements, as seen in patients suffering from a rare disease called mevalonate kinase deficiency (MKD). One of the molecular mechanisms underlying this pathology could depend on the shortage of isoprenoid compounds and the subsequent mitochondrial damage, leading to oxidative stress and pro-inflammatory cytokines’ release. Moreover, it has been demonstrated that cellular death results from the balance between apoptosis and pyroptosis, both driven by mitochondrial damage and the molecular platform inflammasome. In order to rescue the deregulated pathway and decrease inflammatory markers, exogenous isoprenoid compounds were administered to a biochemical model of MKD obtained treating a murine monocytic cell line with a compound able to block the mevalonate pathway, plus an inflammatory stimulus. Our results show that isoprenoids acted in different ways, mainly increasing the expression of the evaluated markers [apoptosis, mitochondrial dysfunction, nucleotide-binding oligomerization-domain protein-like receptors 3 (NALP3), cytokines and nitric oxide (NO)]. Our findings confirm the hypothesis that inflammation is triggered, at least partially, by the shortage of isoprenoids. Moreover, although further studies are necessary, the achieved results suggest a possible role for exogenous isoprenoids in the treatment of MKD.

Treatment of hyperimmunoglobulinemia D syndrome with biologics in children: review of the literature and Finnish experience

“…New insights into the pathogenesis of HIDS provide the basis for currently available biological treatments, as well as for new treatment approaches that are currently only experimental [25,50]. IL-1 plays a key role in the pathogenesis of HIDS, and in accordance with that, the current evidence suggests that the anti-IL-1 agent anakinra is the drug of choice for HIDS in children.…”

“…New insights into the pathogenesis of HIDS pave the way for novel therapeutic options, such as inhibition of Rac-1 or administration of the deficient geranylgeraniol, which have both been shown to decrease IL-1β secretion in cellular models [25,50]. These options result in an inhibition of the overactivation of innate immunity, whereas currently available drugs only suppress the influence of the storm of innate immunity mediators.…”

“…Inflammasomes are activated by pathogen-associated molecular patterns (PAMPS) or damageassociated molecular patterns (DAMPS), such as lipopolysaccharides (LPS) or signals from injured cells [33], and this can explain why infections, vaccines, and stress trigger inflammatory attacks in HIDS. NLRP3 is overexpressed in MVKdeficient patients, and stimulation with LPS in a cellular model of MKD resulted in the induction of NLRP3 and caspase-1 [50]. The complex interplay of cytokines in HIDS is not yet fully understood.…”

Putative modifier genes in mevalonate kinase deficiency

“…Whilst several reports suggest that the shortage of isoprenoid intermediates, including geranylgeraniol, is involved in the autoinflammatory phenotype of MKD, further data has led to a focus of attention on the end products of this pathway, including 25-deoxycholesterol (CH25) (20)(21)(22). Of note, 25-hydroxylcholesterol can act by modulating the mevalonate pathway itself by suppressing sterol regulatory element-binding proteins (SREBPs), thus highlighting a complex feedback network, which may be relevant in the modulation of MKD phenotypes (23,24).…”

HIV Protease Inhibitors Apoptotic Effect in SH-SY5Y Neuronal Cell Line

“…PCR amplification cycle was as follows: after denaturation at 96°C for 10 min, 40 PCR cycles were performed composed by 15 sec at 95°C and a final melting step for 1 min at 60°C. All samples were analyzed in triplicate (for further details see Tricarico et al [18]). …”