Inflammatory profile in X‐linked adrenoleukodystrophy patients: Understanding disease progression

Abstract

X-linked adrenoleukodystrophy (X-ALD) is an inherited disease characterized by progressive inflammatory demyelization in the brain, adrenal insufficiency, and an abnormal accumulation of very long chain fatty acids (VLCFA) in tissue and body fluids. Considering that inflammation might be involved in pathophysiology of X-ALD, we aimed to investigate pro-and anti-inflammatory cytokines in plasma from three different male phenotypes (CCER, AMN, and asymptomatic individuals). Our results showed that asymptomatic patients presented increased levels of proinflammatory cytokines IL-1β, IL-2, IL-8, and TNF-α and the last one was also higher in AMN phenotype. Besides, asymptomatic patients presented higher levels of antiinflammatory cytokines IL-4 and IL-10. AMN patients presented higher levels of IL-2, IL-5, and IL-4. We might hypothesize that inflammation in X-ALD is related to plasmatic VLCFA concentration, since there were positive correlations between C26:0 plasmatic levels and pro-inflammatory cytokines in asymptomatic and AMN patients and negative correlation between anti-inflammatory cytokine and C24:0/ C22:0 ratio in AMN patients. The present work yields experimental evidence that there is an inflammatory imbalance associated Th1, (IL-2, IL-6, and IFN-γ), Th2 (IL-4 and IL-10), and macrophages response (TNF-α and IL-1β) in the periphery of asymptomatic and AMN patients, and there is correlation between VLCFA plasmatic levels and inflammatory mediators in X-ALD. Furthermore, we might also speculate that the increase of plasmatic cytokines in asymptomatic patients could be considered an early biomarker of brain damage and maybe also a predictor of disease progression.

Peroxisomes in Immune Response and Inflammation

“…When the presence of pro- and anti-inflammatory cytokines was measured in the plasma of three different X-ALD phenotypes (asymptomatic, AMN and cALD), a correlation between their concentrations and VLCFA levels was found [90]. Interestingly, also asymptomatic patients have higher plasma levels of pro-inflammatory cytokines (Il-1β, IL-2, IL-8 and TNF-α) compared to the control group [90].…”

“…When the presence of pro- and anti-inflammatory cytokines was measured in the plasma of three different X-ALD phenotypes (asymptomatic, AMN and cALD), a correlation between their concentrations and VLCFA levels was found [90]. Interestingly, also asymptomatic patients have higher plasma levels of pro-inflammatory cytokines (Il-1β, IL-2, IL-8 and TNF-α) compared to the control group [90]. On the other hand, anti-inflammatory cytokines, such as IL-4, were found in AMN and asymptomatic patients, while the IL-10 concentration was significantly higher in asymptomatic patients than AMN, cALD, and the controls [90].…”

“…Interestingly, also asymptomatic patients have higher plasma levels of pro-inflammatory cytokines (Il-1β, IL-2, IL-8 and TNF-α) compared to the control group [90]. On the other hand, anti-inflammatory cytokines, such as IL-4, were found in AMN and asymptomatic patients, while the IL-10 concentration was significantly higher in asymptomatic patients than AMN, cALD, and the controls [90]. Only AMN patients had very high levels of IL-5.…”

Increased levels of hexacosanoic acid in the brain of Wistar rats: a behavioral study

“…In this work, we verified that Wistar rats that received an intraperitoneal administration of C26:0 and were sacrificed after 45 minutes presented a mean brain C26:0 level of 1.37 µmol/L, which would approach plasmatic levels of male X-ALD patients. In humans, X-ALD is usually diagnosed by measuring VLCFA levels in plasma 13 ; male patients present a mean range of 1.36-4.94 µmol/L of C26:0, female heterozygotes have a mean range of 1.41-2.33 µmol/L, and healthy individuals present a mean range of 0.11-0.96 µmol/L 15 .…”

Peroxisome quality control and dysregulated lipid metabolism in neurodegenerative diseases

“…PPAR agonists, such as pioglitazone, can ameliorate AD-related pathology and improve cognition by decreasing Aβ production 105,106 . PPAR agonists also inhibit inflammatory gene expression and immune responses and inhibit the secretion of proinflammatory cytokines 107,108 . Icariin, a prenylated flavonol glycoside found in various medicinal herbs, attenuates M1 microglial activation and Aβ plaque formation in the hippocampus and prefrontal cortex by increasing PPARγ levels in an AD mouse model 109,110 .…”