Dyslipidemia Associated with Atherosclerotic Disease Systemically Alters Dendritic Cell Mobilization

Abstract

High LDL and/or low HDL are risk factors for atherosclerosis and are also a common clinical feature in systemic lupus erythematosus, rheumatoid arthritis, and psoriasis. Here, we show that changes in lipid profiles that reflect atherosclerotic disease led to activation of skin murine dendritic cells (DCs) locally, promoted dermal inflammation, and induced lymph node hypertrophy. Paradoxically, DC migration to lymph nodes was impaired, suppressing immunologic priming. Impaired migration resulted from inhibitory signals generated by platelet-activating factor (PAF) or oxidized LDL that acts as a PAF mimetic. Normal DC migration and priming was restored by HDL or HDL-associated PAF acetylhydrolase (PAFAH), which mediates inactivation of PAF and oxidized LDL. Thus, atherosclerotic changes can sequester activated DCs in the periphery where they may aggravate local inflammation even as they poorly carry out functions that require their migration to lymph nodes. In this context, HDL and PAFAH maintain a normally functional DC compartment.

Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficient mice

“…32), there could either be removal of inhibitory lipids by HDL or their enzymatic detoxification. The latter possibility is consistent with our recent report that skin DC migration was increased in apoE Ϫ/Ϫ mice by infusion of HDL-associated PAF-AH (31).…”

“…In particular, PAF and PAF-like lipids inhibit DC migration (5,31). With the relative increase in the regression environment in HDL (and PAF-AH; ref.…”

Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

“…Its production is controlled by the activity of PAF acetylhydrolases. Thus, because HDL and HDL‐associated PAF acetylhydrolase (PAF‐AH) has been shown to restore normal dendritic cell migration and priming,52 we sought to determine whether an increase in PAF‐AH activity could have accounted for the beneficial effect on platelet activity, and consequently, on lymphatic vessel integrity. Figure S5 rather shows that PAF‐AH activity, either in plasma or in lymph, is unchanged among the 3 different groups of Ldlr −/− mice, suggesting that apoA‐I does not mediate its beneficial effect on lymphatic function via a PAF‐AH‐related mechanism.…”

Expansion of Cortical and Medullary Sinuses Restrains Lymph Node Hypertrophy during Prolonged Inflammation

“…Undesirable situations, including LN hypertrophy and hyperactivation, which are often associated with autoimmune and chronic inflammatory diseases, may arise if these lymphocytes fail to leave the inflamed LNs in a timely manner. Indeed, we have some evidence that the LN hypertrophy described in dyslipidemic mice (44) mainly results from the complete block of lymphocyte egress from the inflamed LNs (M.H. Tay and V. Angeli, unpublished observations).…”