Hyaluronan fragments modulate inflammation in preeclampsia: a focus on Th17/Treg balance

Pregnant women with preeclampsia (PE) exhibit an exacerbated inflammatory immune response. Hyaluronan (HA), a damage-associated molecular pattern (DAMP), is increased in the plasma of women with PE and may differentially modulate immune responses depending on its molecular weight. Forty-five women were investigated, including 20 with PE, 20 normotensive (NT) pregnant women, and 5 healthy non-pregnant (NP) women. Plasma samples were obtained for TNF, IL-10, HA, and soluble CD44 (sCD44) analyses by ELISA. Expression of the CD44 receptor, as well as intracytoplasmic transcription factors T-bet (Th1), RORγt (Th17), Foxp3 (Treg), and NF-κB, and intracellular cytokines TNF, IL-17, and IL-10, was assessed by flow cytometry. Experiments were conducted on peripheral blood mononuclear cells, followed by cell culture with or without LMW-HA or high-molecular-weight HA (HMW-HA). Pregnant women with PE showed elevated plasma concentrations of HA and TNF, while sCD44 and IL-10 levels were lower than in the NT group. The percentage of CD44-expressing cells was higher among lymphocytes expressing T-bet, RORγt, TNF, and IL-17. Cell stimulation with LMW-HA increased T-bet and RORγt and decreased FoxP3 expression in NT women. LMW-HA stimulation induced higher NF-κB p65 expression in cells from the NP group. Conversely, cell stimulation with HMW-HA decreased RORγt, IL-17, and TNF expression, while increasing FoxP3 and IL-10 expression in preeclamptic women. Overall, HA molecular weight differentially modulated inflammatory- and regulatory-associated markers, with HMW-HA favoring a more regulatory profile and shifting the inflammatory state toward a regulatory-associated profile.