Alterations in circulating monocyte and neutrophil populations in Abcd1- mice, a murine model of X-linked adrenoleukodystrophy Jonathan D. Proto1, Lisa Woodworth2, Nellwyn Hagan2, Jacqueline Saleh2, Jose Sancho2, John Leonard1, Mandy Cromwell1*, 1Rare Disease Research, 2Neurobiology Research, Sanofi, Framingham, MA *Corresponding Author
X-linked adrenoleukodystropy (X-ALD) is a peroxisomal disorder caused by loss of function of the very-long chain fatty acid (VLCFA) transporter, ABCD1. In the absence of functional ABCD1, peroxisomal beta-oxidation of VLCFA, especially C26:0, is severely impaired. The accumulation of VLCFA in the CNS and adrenal glands is thought to result in the symptoms of X-ALD, which range from childhood onset inflammatory cerebral demyelination (cCALD) to adult onset adrenomyeloneuropathy (AMN), which may or may not have cerebral involvement. It is currently unknown why cCALD occurs in a subset of patients. The Abcd1 deficient (Abcd1-)mouse develops an AMN-like phenotype at approximately 16 months of age, but no changes in the brain have been reported. Interestingly, Abcd1 is reported to be highly expressed in circulating neutrophils and monocytes. Thus, we investigated whether alterations in these populations occurred in Abcd1- mice. Surprisingly, we found that by post-natal day 4, monocytes (CD115+CD11b+) were elevated in both peripheral circulation (~34% increase, p<0.05) and spleens (~72% increase, p<0.05) of Abcd1- mice. Likewise, neutrophil (Ly-G6+CD11b+) populations were also perturbed. Flow cytometry analysis of adult (14-16 weeks) Abcd1- brains revealed that monocytes were significantly elevated (~2 fold increase, p<0.05), concomitant with a significant increase in microglia (~30% increase, p<0.05), and a trend for increased neutrophils (2.6 fold increase, p=0.07). Following in vitro stimulation with IFNy and a TLR4 agonist, Abcd1-microglia expressed higher surface levels of MHCII and the costimulatory molecule CD40 compared to WT, suggesting naïve Abcd1-microglia are in a primed state. Future investigations aim to interrogate the signal(s) recruiting leukocytes to the brains of Abcd1- mice and what role these populations play in microglial proliferation and activation. Given recent reports suggesting that blood brain barrier function may be compromised in X-ALD patients preceding cerebral demyelination, our findings support further investigation into the role of peripheral leukocytes in the CNS pathologies of X-ALD.
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