SREBP1c modulates Treg immunobiology through a phospholipid-dependent adenosine pathway
Fabrizia Bonacina, Claudio Procaccini, Marta Iaia, Arianna Moretti, Monika Svecla, Silvia Pedretti, Jeroen Bogie, Giovanni Battista Vingiani, Annalisa Moregola, Francesca Genova, Claudia Russo, Giusy De Rosa, Claudia La Rocca, Giada Mondanelli, Marco Gargaro, Nico Mitro, Giuseppe Matarese, Giuseppe Danilo Norata
Fabrizia Bonacina, Claudio Procaccini, Marta Iaia, Arianna Moretti, Monika Svecla, Silvia Pedretti, Jeroen Bogie, Giovanni Battista Vingiani, Annalisa Moregola, Francesca Genova, Claudia Russo, Giusy De Rosa, Claudia La Rocca, Giada Mondanelli, Marco Gargaro, Nico Mitro, Giuseppe Matarese, Giuseppe Danilo Norata
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Research Article Immunology Metabolism

SREBP1c modulates Treg immunobiology through a phospholipid-dependent adenosine pathway

Abstract

Tregs maintain immune tolerance through mechanisms tightly coupled to cellular metabolism. Whereas glycolysis supports migration of Tregs, lipid metabolism sustains their suppressive phenotype. Here, we identify SREBP1c as a central regulator of Treg immunobiology. Tregs from Srebp1c-deficient mice displayed impaired suppressive function, reduced frequencies in circulation and lymphoid tissues, and diminished expression of functional markers. These defects stemmed from intrinsic metabolic rewiring rather than systemic alterations, as both ex vivo Tregs (CD4+CD25hiFoxP3+) and in vitro–derived Tregs lacking Srebp1c were shifted toward glycolysis. Integrated transcriptomic and lipidomic analyses revealed that Srebp1c-deficient Tregs exhibited defective phospholipid remodeling, with an accumulation of lysophosphatidylcholines over phosphatidylcholines, which we attributed to enhanced cytosolic phospholipase A2 (cPLA2α) activity and disruption of the Lands cycle. Altered lipid composition impaired adenosine-mediated immunosuppression by reducing CD73 expression and extracellular adenosine generation. Accordingly, pharmacological inhibition of cPLA2α restored adenosine signaling, CD73 expression, and Treg suppressive capacity. Thus, by preserving phospholipid homeostasis, SREBP1c functions as an immunometabolic checkpoint that links lipid metabolism to adenosine-dependent Treg suppression.

Authors

Fabrizia Bonacina, Claudio Procaccini, Marta Iaia, Arianna Moretti, Monika Svecla, Silvia Pedretti, Jeroen Bogie, Giovanni Battista Vingiani, Annalisa Moregola, Francesca Genova, Claudia Russo, Giusy De Rosa, Claudia La Rocca, Giada Mondanelli, Marco Gargaro, Nico Mitro, Giuseppe Matarese, Giuseppe Danilo Norata

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Figure 6

Srebp1c-mediated phospholipid homeostasis supports adenosine metabolism.

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Srebp1c-mediated phospholipid homeostasis supports adenosine metabolism...
(A) Graphic representation of acyl-chain remodeling of phospholipids by the Lands cycle: phospholipase A2 (PLA2) removes an acyl-CoA from a phosphatidylcholine (PC), generating a lysophosphatidylcholine (LPC); then, the LPC acyltransferase (LPCAT) transfers an Acyl-Coa to an LPC to form a PC. (B) Quantification of p-cPLA2α by Western Blot analysis. Data are corrected on β-actin abundance; a representative Western blot for p-cPLA2α and β-actin is shown. (C) Concentration of adenosine in the supernatants of iTregs treated or not with the cPLA2α inhibitor pyrrophenone (10 nM for 3 h). (D) Graphic representation of adenosine metabolism: extracellular ATP is hydrolyzed by CD39 to AMP (via an ADP intermediate), which is then converted to adenosine by CD73. (E) Expression of CD73 by flow cytometry in iTregs treated or not with the cPLA2α inhibitor pyrrophenone (10 nM for 3 h). (F) Suppression of Tconv proliferation by iTregs pretreated or not with the cPLAα inhibitor MAFP (5 μM for 3 h) at increasing ratios with T conventional cells (0:1 indicates that no Tregs were used, while 1:4, 1:2, and 1:1 indicate the proportion of iTregs to Tconv) for 3 days. Representative histograms from flow cytometry are shown. (G) ECAR analysis by glucose stress test tested by Seahorse on iTregs pretreated or not with the cPLA2α inhibitor pyrrophenone (10 nM for 3 h). (H) Expression of CD36 in iTreg pretreated or not with the cPLA2α inhibitor pyrrophenone (10 nM for 3 h). Representative histograms from flow cytometry analysis are shown. N = 3–8/group. Data are presented as mean ± SEM. Statistical analysis has been performed with unpaired nonparametric t test (B) or 2-way ANOVA (C, E, F, and H).