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Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Splenic marginal zone B (MZB) cells, positioned at the interface between circulating blood and lymphoid tissue, detect and respond to blood-borne antigens. Here we show that MZB cells in mice activate a homeostatic program in response to a high-cholesterol diet (HCD) and regulate both the differentiation and accumulation of T follicular helper (TFH) cells. Feeding mice an HCD resulted in upregulated MZB cell surface expression of the immunoregulatory ligand PDL1 in an ATF3-dependent manner and increased the interaction between MZB cells and pre-TFHcells, leading to PDL1-mediated suppression of TFHcell motility, alteration of TFHcell differentiation, reduced TFHabundance and suppression of the proatherogenic TFHresponse. Our findings reveal a previously unsuspected role for MZB cells in controlling the TFH–germinal center response to a cholesterol-rich diet and uncover a PDL1-dependent mechanism through which MZB cells use their innate immune properties to limit an exaggerated adaptive immune response.

Introduction:Tafazzin acylates immature monolysocardiolipin to form mature cardiolipin. Cardiolipin is the signature phospholipid of the mitochondrial inner membrane required for respiratory efficiency and regulation of apoptosis. Mitochondrial respiration is reduced in atherosclerosis. However, whether tafazzin regulates vascular smooth mucle cell (VSMC) mitochondrial function and contributes to atherosclerosis is unclear.Hypothesis:Tafazzin regulates VSMC mitochondrial function and atherosclerosis development.Methods:We examined tafazzin expression and regulation in human plaques and VSMCs. We determined the in vitro effects of tafazzin using siRNA mediated cell silencing or lentiviral infection to express either tafazzin (Taz) or tafazzin with a transacylase defective mutation (TazH69Q). We also generated mice expressing VSMC restricted Taz or TazH69Qand crossed them with apolipoprotein E deficient mice (SM22α-Taz/ApoE-/-or SM22α-TazH69Q/ApoE-/-) to study tafazzin in vivoResults:Tafazzin mRNA and protein is decreased in plaque and plaque VSMCs. MicroRNA 125a-5p expression is increased in plaques, downregulates tafazzin expression and is induced by oxidised low density lipoprotein. Tafazzin silencing and expression of TazH69Qreduces mitochondrial respiration, decreases ATP content (0.13±0.01nmoles vs 0.21±0.01nmole, n=4), and promotes apoptosis. SM22α-TazH69Q/ApoE-/-mice showed increased plaque burden (28±2.3% vs 17±2.1%, n=17), increased necrotic core and reduced fibrous cap areas. In contrast, over-expression of tafazzin increases VSMC mitochondrial respiration and protects against apoptosis. SM22α-Taz/ApoE-/-mice showed no change in plaque burden but increased features of plaque stability. SS-31, which binds and stabilises cardiolipin, improves mitochondrial respiration and decreases apoptosis in SM22α-TazH69Q/ApoE-/-VSMCs.Conclusions:Tafazzin expression is decreased in plaque VSMCs and is negatively regulated by microRNA 125a-5p. Defective tafazzin decreases mitochondrial respiration, increases apoptosis and promotes atherosclerosis. Tafazzin is therefore an important and unrecognised regulator of VSMC mitochondrial function and atherosclerosis.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.