Anti‐Inflammatory Liver X Receptors and Related Molecules in Multiple Sclerosis Patients from Sardinia and Sweden

Huang, Y.‐M.; Liu, X.; Steffensen, K.; Sanna, A.; Arru, G.; Sominanda, A.; Sotgiu, S.; Rosati, G.; Gustafsson, J.‐Å.; Link, H.

The nuclear receptor heterodimers of liver X receptors (LXRs) are recently identified as key transcriptional regulators of genes involved in lipid homeostasis and inflammation. LXRs and their ligands are negative regulators of macrophage inflammatory gene expression. Multiple sclerosis (MS), a demyelinating disease of the central nervous system of unknown cause, is characterized by recurrent inflammation involving macrophages and their inflammatory mediators. Sweden belongs to the countries with a high MS incidence. In Italy, incidence is lower, with an exception for Sardinia where the incidence is even higher than that in Sweden. Subjects from Sardinia are ethnically more homogeneous and differ from Swedes, also regarding genetic background and environment. We studied LXRs and their related molecules of blood mononuclear cells (MNCs) from female patients with untreated relapsing‐remitting MS from Sassari, Sardinia and Stockholm, Sweden. Sex‐ and age‐matched healthy controls (HCs) were from both areas. mRNA expression was evaluated by real‐time PCR. LXR‐α was lower (P < 0.05) in MS (mean ± SEM: 3.1 ± 0.2; n = 37) compared to HC (3.6 ± 0.1; n = 37). LXR‐α was lower in MS from Stockholm (2.6 ± 0.2; n = 22) compared to corresponding HC (3.4 ± 0.1; n = 22; P < 0.01) and compared to MS (3.8 ± 0.2; n = 15; P < 0.001) and HC (4 ± 0.2; n = 15; P < 0.001) from Sardinia. MS patients from Stockholm, but not from Sassari, also expressed lower (P < 0.05) LXR‐β (−4.1 ± 0.4) compared to corresponding HC (−2.9 ± 0.3). MS from Stockholm was associated with higher ABCA‐1 (6.1 ± 0.4 versus 5.0 ± 0.3; P < 0.05) and higher estrogen receptor‐β‐Cx (2.4 ± 0.4 versus 0.8 ± 0.4; P < 0.01) compared to corresponding HC. The HC from Sassari had higher androgen receptor (2.9 ± 0.2) compared to MS from Sassari (1.4 ± 0.3; P < 0.01), MS (1.3 ± 0.4; P < 0.01) and HC from Stockholm (1.2 ± 0.3; P < 0.01). MS from Sassari had lower cyclooxygenase‐1 compared to corresponding HC (5.1 ± 0.4 versus 6.6 ± 0.3; P < 0.01) and lower prostaglandin‐E (−0.03 ± 0.5) compared to the HC (1.4 ± 0.5; P < 0.05) and MS (2.7 ± 0.4; P < 0.05) and HC from Stockholm (1.9 ± 0.4, P < 0.001). Our findings identify LXRs and their related molecules as being involved in MS from Stockholm but not from Sassari, while sex hormone receptors seem to be involved in MS in Sassari.