Editors' ChoiceAutoimmunity

A fatty link between heart disease and autoimmunity

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Science Translational Medicine  23 May 2018:
Vol. 10, Issue 442, eaat8535
DOI: 10.1126/scitranslmed.aat8535


Atherogenic hyperlipidemia drives IL-27 production by dendritic cells to support follicular T cell differentiation and systemic autoimmune disorders in mice.

It has long been recognized that systemic lupus erythematosus (SLE) is associated with elevated incidence of atherosclerosis, the major cause of cardiovascular disease. Atherosclerosis is characterized by increased circulating lipids (hyperlipidemia), including cholesterol/triglycerides–carrying low-density lipoprotein (LDL). However, how atherogenic environment contributes to SLE disease progression has been unclear. Cholesterol-lowering treatments, such as statins, modestly ameliorate SLE, illustrating a potential impact of hyperlipidemia on SLE progression.

To enable mechanistic understanding of atherosclerosis-associated SLE, Ryu and colleagues generated novel mouse models by reconstituting the hematopoietic system of atherosclerosis-prone mice with bone marrow from a SLE-prone mouse strain. These chimeric mice developed accelerated lupus-like symptoms, similar to SLE patients with atherosclerosis. Careful examination of their immune system revealed that they had increased T follicular helper (TFH) cells, which drive germinal center formation and pathologic antibody production from B cells. The authors identified interleukin-27 (IL-27), secreted from a subset of dendritic cells (DCs), as a driver for the increased TFH differentiation. Furthermore, specific lipid species, such as oxidized LDL, in an atherogenic hyperlipidemic environment engaged toll-like receptor 4 (TLR4) on DCs to promote IL-27 production; accumulation of lipids alone, as in the case of high-fat diet–induced obesity model, did not induce IL-27. Deficiency of either IL-27, IL-27 receptor, or IL-27 signaling molecules in immune system blocked TFH accumulation in the chimeric mouse model, demonstrating that IL-27 is necessary for the increased TFH differentiation and B cell activation during hyperlipidemia. Importantly, people with high circulating cholesterol had increased serum IL-27 and antibodies compared with healthy controls, indicating that a similar mechanism may operate in humans.

Altogether, this work elucidates the potential immunological basis of the high incidence of atherosclerosis in SLE patients and further identifies a critical cytokine necessary for development of atherosclerosis-related SLE. It should be noted that IL-27 also exhibits anti-inflammatory functions under different circumstances, suggesting that its proinflammatory function may be unique in the atherogenic environment. Whether IL-27 can be targeted for therapeutic purpose in SLE patients with hyperlipidemia warrants further investigation.

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