TWEAK is expressed at the cell surface of monocytes during multiple sclerosis

Abstract

The TNF superfamily ligand, TNF-like weak inducer of apoptosis (TWEAK), regulates cellular responses ranging from proliferation to cell death in a manner highly dependent on the cell type and the microenvironmental context. We have shown previously that treatment of experimental autoimmune encephalomyelitis mice after the priming phase with neutralizing anti-TWEAK antibodies results in a reduction in the severity of the disease and leukocyte infiltration. To further characterize TWEAK/fibroblast growth factor-inducible 14-kDa protein (Fn14) involvement during multiple sclerosis (MS), we evaluated in MS patients and controls: TWEAK and Fn14 expression on PBMC and soluble TWEAK concentration in serum and cerebrospinal fluid (CSF). Thirty-six consecutive patients were enrolled, including 11 patients with relapsing-remitting MS, 11 with a clinical isolated syndrome suggestive of MS (CISSMS), and 14 controls with non-MS diseases. Intracellular TWEAK could be observed in lymphocytes and/or monocytes in all groups of patients. None of the 36 patients displayed TWEAK expression at the cell surface of lymphocytes. In contrast, 12 out of the 36 patients were positive for membrane TWEAK expression on their monocytes. Among these patients, eight were from the CISSMS group. Fn14 was not detected in PBMC. The soluble form of TWEAK is detectable in serum and CSF of patients, and TWEAK concentrations were not statistically different between the disease groups. We demonstrated for the first time that TWEAK is expressed at the cell surface of monocytes during MS, especially in the CISSMS group. Our results support the proposal that TWEAK could be a target for antibody therapy in MS.

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) Mediates p38 Mitogen-Activated Protein Kinase Activation and Signal Transduction in Peripheral Blood Mononuclear Cells from Patients with Lupus Nephritis

“…Recently, research has revealed that TWEAK could be observed in lymphocytes and/or monocytes in patients with multiple sclerosis [47], and cell-surface expression of TWEAK has also been reported on human monocytes after IFN exposure in culture [48] and on T cells from patients with systemic lupus erythematosus [32,49]. Intracellular TWEAK could be observed in lymphocytes (T cells and B cells) and monocytes from SLE patients [50]. Fn14 receptor is the cognate receptor for TWEAK.…”

“…TWEAK mRNA is ubiquitously expressed, and the expression is increased after injury including in LN [5,9,21,33,36,[39][40][41][42]. It is thought to be expressed primarily as a soluble cytokine as a result of efficient furin-mediated cleavage along the secretory pathway [43], largely produced as a soluble cytokine by immune cell types [44,45], such as monocytes/macrophages, dendritic cells, and natural killer cells [46,47]. Recently, research has revealed that TWEAK could be observed in lymphocytes and/or monocytes in patients with multiple sclerosis [47], and cell-surface expression of TWEAK has also been reported on human monocytes after IFN exposure in culture [48] and on T cells from patients with systemic lupus erythematosus [32,49].…”

Diminished production of TWEAK by the peripheral blood mononuclear cells is associated with vascular involvement in patients with systemic sclerosis.

“…Since monocytes/macrophages have been shown to express TWEAK [11] we hypothesized that increased production of TWEAK by the peripheral blood mononuclear cells (PBMC) might be a source of increased levels of TWEAK in the blood of SSc patients. To address this hypothesis, the production of TWEAK was investigated in the PBMC from patients with SSc and healthy controls.…”

TWEAK stimulation of kidney resident cells in the pathogenesis of graft versus host induced lupus nephritis

“…Furthermore, activated renal macrophages are markers of disease onset in lupus nephritis [15]. We hypothesized that macrophages, as a result of both FcR engagement by immune complexes deposited in the glomeruli [16], Fn14 engagement by TWEAK, and/or active secretion of TWEAK [4][5][6], would play a critical role in initiating and amplifying the inflammatory cascade that culminates in lupus nephritis, and that their depletion would reveal this unique role by effectively reducing kidney damage.…”

“…The cytokine TWEAK (TNF-like weak inducer of apoptosis) is a member of the TNF superfamily that is expressed in a wide variety of organs [1][2][3] and has been detected at the mRNA or protein level in monocytes/macrophages [4][5][6], kidney tubular cells, endothelial cells, astrocytes, microglia, and certain tumor cell lines [1][2][3]. Its cognate receptor, Fn14, is generally expressed at very low levels in normal tissue, but is highly upregulated in a wide range of organs in contexts of injury and disease [2,3] As mRNA or as protein, Fn14 can be expressed by monocytes/macrophages [6], endothelial cells [7], mesangial cells [8,9], and podocytes [9].…”