TACI-deficient macrophages protect mice against metaflammation and obesity-induced dysregulation of glucose homeostasis

Abstract

Transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) is a receptor for the TNF superfamily cytokines, B cell-activating factor (BAFF), and A proliferation-inducing ligand (APRIL). Here, we demonstrate that TACI-deficient mice subjected to high-fat diet (HFD) are protected from weight gain and dysregulated glucose homeostasis. Resistance to HFD-induced metabolic changes in TACI-deficient mice does not involve TACI-mediated adipogenesis. Instead, accumulation of M2 macrophages (Mfs), eosinophils, and type 2 innate lymphoid cells in visceral adipose tissue (VAT) is implicated in the protection from obesity-induced assaults. In support of this hypothesis, adoptively transferred TACI-deficient peritoneal or adipose tissue Mfs, but not B cells, can improve glucose metabolism in the obese host. Interestingly, the transferred TACI-deficient Mfs not only home to host VAT but also trigger the accumulation of host M2 Mfs and eosinophils in VAT. The increase in host M2 Mfs in VAT is likely a result of eosinophil recruitment in response to eotaxin-2 produced by TACI-deficient Mfs. Insulin signaling experiments revealed that IL-10 secreted by TACI-deficient Mfs is responsible for maintaining adipocyte insulin sensitivity. Thus, the adoptive transfer experiments offer a model where TACI-deficient Mfs accumulate in VAT and protect against metaflammation and obesity-associated dysregulation of glucose metabolism.