Intravenous injection of lipid-free apolipoprotein A-I dampens inflammation by reprogramming macrophage function

BACKGROUND: High-density lipoproteins (HDL) and their main protein apolipoprotein A-I (apoA-I) have been implicated as immunomodulators. However, their precise effects on vascular and immune cells during tissue homeostasis and responses to danger signals are incompletely understood. Here, we show that apoA-I may dampen inflammation by modulating perivascular macrophage (PVM) function.

METHODS: In the present study, a combination of intravital microscopy, flow cytometry, experimental ex vivo models, and bulk RNA sequencing was used to study the immunomodulatory capacity of apoA-I. Representative mouse models of acute inflammation and chronic arthritis were used to determine how apoA-I in vivo affects target tissue inflammation under various inflammatory settings.

RESULTS: Using intravital imaging, we observed specific uptake of intravenously injected lipid-free apoA-I by dermal PVMs. Supraphysiological doses of apoA-I altered key cellular pathways, directed by mTORC1 and IRF8 programs, in THP-1 derived macrophages. In LPS-induced cutaneous inflammation, pretreatment of mice with apoA-I resulted in enhanced fluid drainage from the dermis, decreased availability of inflammatory cues, and reduced immune cell trafficking in and out of the skin. Moreover, apoA-I reduced joint inflammation in human TNF-transgenic mice, a spontaneous model of polyarthritis that resembles rheumatoid arthritis (RA).

CONCLUSION: ApoA-I acts as an integrator of vascular–immune interactions by modulating macrophage function in the vicinity of blood vessels. These findings open avenues for HDL-targeting strategies in a broad spectrum of autoimmune disorders, including RA.