Adipocytes as Immune Cells: Differential Expression of TWEAK, BAFF, and APRIL and Their Receptors (Fn14, BAFF-R, TACI, and BCMA) at Different Stages of Normal and Pathological Adipose Tissue Development

Abstract

Adipose tissue represents a rich source of multipotent stem cells. Mesenchymal cells, isolated from this source, can differentiate to other cell types in vitro and therefore can be used for a number of regenerative therapies. Our view of adipose tissue has recently changed, establishing adipocytes as new members of the immune system, as they produce a number of proinflammatory cytokines (such as IL-6 and TNFα and chemokines, in addition to adipokines (leptin, adiponectin, resistin) and molecules associated with the innate immune system. In this paper, we report the differential expression of TNF-superfamily members B cell activating factor of the TNF Family (BAFF), a proliferation inducing ligand (APRIL), and TNF-like weak inducer of apoptosis (TWEAK) in immature-appearing and mature adipocytes and in benign and malignant adipose tissue-derived tumors. These ligands act through their cognitive receptors, BAFF receptor, transmembrane activator and calcium signal-modulating cyclophilic ligand (TACI), B cell maturation Ag (BCMA), and fibroblast growth factor-inducible 14 (Fn14), which are also expressed in these cells. We further report the existence of functional BCMA, TACI, and Fn14 receptors and their ligands BAFF, APRIL, and TWEAK on adipose tissue-derived mesenchymal cells, their interaction modifying the rate of adipogenesis. Our data integrate BAFF, APRIL, and TWEAK and their receptors BCMA, TACI, and Fn14 as novel potential mediators of adipogenesis, in addition to their specific role in immunity, and define immature and mature adipocytes as source of immune mediators.

B-cell activating factor (BAFF) — a new factor linking immunity to diet?

“…This is consistent with observations that adipocytes are capable of producing BAFF and that they carry BAFF receptors capable of binding BAFF [3,4]. The pivotal role of BAFF in adipogenesis has recently been proposed [12] and the site-dependant differences in BAFF expression might possibly contribute to differences in body fat distribution, making patients with higher BAFF circulating levels more prone to develop abdominal obesity than the others.…”

“…Furthermore, those authors reported a considerable difference in mRNA and protein expression between epididymal tissue and visceral adipose tissue [11]. In a study by other authors, the presence of all known BAFF receptors (BAFF-R, BCMA, and TACI) was confirmed in adipocytes, and their expression was upregulated during adipocyte differentiation [12]. To summarize, it is highly likely that, apart from its role in the immune system, BAFF can be also considered an adipokine, which might have potentially huge consequences for comprehension of immune mechanisms within the white adipose tissue (WAT).…”

Deficiency of Fibroblast Growth Factor-Inducible 14 (Fn14) Preserves the Filtration Barrier and Ameliorates Lupus Nephritis

“…58 The final expression levels of target genes were normalized to glyceraldehyde-3-phosphate dehydrogenase values, and the values were multiplied by 10 2 or 10 3 for display purposes. Primer sequences are listed in Supplemental Table 1.…”

APRIL Binding to BCMA Activates a JNK2–FOXO3–GADD45 Pathway and Induces a G2/M Cell Growth Arrest in Liver Cells

“…APRIL has been reported to bind also the proteoglycan syndecan-1 (CD138) (16,17), and a not-yet-identified APRIL receptor has been advanced, as well (18,19). This complex system of two ligands and (at least) three receptors was considered exclusive to B lymphocytes; however, recently, all or some of these five molecules have been identified in mesenchymal cells (20), normal tissues (20)(21)(22)(23)(24), and epithelial tumors (20,21,(24)(25)(26), suggesting additional non-immune cellrelated functions for these ligands and receptors, in both physiological and malignant tissues. APRIL has also been found to be expressed in some normal germinal-center B cells, myeloid and dendritic cells, malignant B cells and cell lines, activated T cells, glioblastoma cell lines, and the placenta (1,18,(27)(28)(29)(30)(31)(32)(33).…”

“…APRIL has also been found to be expressed in some normal germinal-center B cells, myeloid and dendritic cells, malignant B cells and cell lines, activated T cells, glioblastoma cell lines, and the placenta (1,18,(27)(28)(29)(30)(31)(32)(33). BAFF has also been detected in some of these tissues, but no significant differences between normal and neoplastic tissue are usually reported; the expression of its cognate receptor BAFFR is either missing or occurs independently of tumor evolution (20,21,(24)(25)(26). Binding of APRIL or BAFF to BCMA or TACI triggers diverse signaling pathways in engineered cells, including nuclear translocation of NF-kB, activation of p38 mitogen-activated kinase and JNK phosphorylation for BCMA (34), and NF-kB nuclear translocation and JNK phosphorylation for TACI (11).…”