Myeloid ADAM17 induces ST2⁺ T regulatory cells that limit obesity-induced metabolic inflammation through changes in...

Obesity is a detrimental disease that affects almost all physiological functions of the person that is afflicted. Secreted TNF alpha (sTNF) levels are directly correlated in obesity with weight gain and morbidity, as well as metabolic dysregulation.¹ ADAM17 cleaves membrane TNF alpha (mTNF) into its soluble form, sTNF. This is well defined, but the mechanisms in metabolic dysregulation behind the regulation of TNF, the source of TNF, as well as the downstream action of TNF is less clear. Here, we demonstrate a bifunctional role of TNF, with both sTNF and mTNF having distinct action on adipose T regulatory cells (T_regs). First, we show that modulation of TNF on macrophages in mice where ADAM17 is deleted from the myeloid lineage (ADAM17^LysM) have a significant metabolic advantage as illustrated by an increase in glucose tolerance and decrease in body weight. Next, deep immune phenotyping of the fatpad of these mice after high fat diet (HFD) illustrated that there was an increased recruitment and activation of ST2⁺ T regulatory cells (T_regs). Utilizing mice with TNF deleted from the myeloid lineage (TNF^lysM), we were able to show that the accumulation and activation of these T_regs occurred through two separate mechanistic actions of TNF. One, sTNF regulates this T_reg population through action on adipocytes that results in soluble ST2 (sST2) production. Two, mTNF on macrophages further potentiates these cells through increased IL-33 production. This work additionally suggests that targeting the mTNF:TNFR2 axis may be a beneficial for improving metabolic health in obesity.