Aberrant levels and function of the potent anti-inflammatory high-density lipoprotein (HDL) and accelerated atherosclerosis have been reported in patients with autoimmune inflammatory diseases. Whether HDL affects the development of an autoimmune response remains elusive. Herein, we utilized apolipoprotein A-I deficient (apoA-I-/-) mice, characterized by diminished circulating HDL levels, to delineate the role of HDL in autoimmunity. ApoA-I-/-mice exhibited increased severity of antigen-induced arthritis compared to wild-type mice and this was associated with elevated Th1 and Th17 cell reactivity in the draining lymph nodes (dLNs). Furthermore, reconstituted HDL (rHDL) attenuated IFN-γ and IL-17 secretion by antigen-specific T cells upon stimulation of dLNs in vitro. The suppressive effects of rHDL were mediated through modulation of dendritic cell (DC) function. Specifically, rHDL-treated DCs demonstrated an immature phenotype characterized by downregulated co-stimulatory molecules, the release of low amounts of pro-inflammatory cytokines, and failure to promote T cell proliferation in vitro. The mechanism of action involved the inhibition of NF-κB nuclear translocation and the decrease of Myd88 mRNA levels by rHDL. Finally, modulation of DC function by rHDL was critically dependent on the presence of SR-BIand ABCA1 but not of the ABCG1 transporter. These findings reveal a novel role of HDL in the regulation of adaptive inflammatory responses through suppression of DC function that could be exploited therapeutically in autoimmune inflammatory diseases.

KLK4, a serine esterase with putative renoprotective properties, is down-regulated by miR-422a in LN kidney suggesting that, in addition to immune activation, local factors may be implicated in the disease.

No abstract

No abstract