Anti-CCL21 monoclonal antibody

TNF-like weak inducer of apoptosis (TWEAK) receptor Fn14 is expressed by podocytes and Fn14 deficiency protects from experimental proteinuric kidney disease. However, the downstream effectors of TWEAK/Fn14 in podocytes are poorly characterized. We have explored TWEAK activation of non-canonical NF kappa B signaling in cultured podocytes. In cultured podocytes, TWEAK increased the expression of the chemokines CCL21, CCL19 and RANTES in a time-dependent manner. The inhibitor of canonical NF kappa B activation parthenolide inhibited the CCL19 and the early RANTES responses, but not the CCL21 or late RANTES responses. In this regard, TWEAK induced non-canonical NF kappa B activation in podocytes, characterized by NF kappa B2/p100 processing to NF kappa B2/p52 and nuclear migration of RelB/p52. Silencing by a specific siRNA of NIK, the upstream kinase of the non-canonical NF kappa B pathway, prevented CCL21 upregulation but did not modulate CCL19 or RANTES expression in response to TWEAK, thus establishing CCL21 as a non-canonical NF kappa B target in podocytes. Increased kidney Fn14 and CCL21 expression was also observed in rat proteinuric kidney disease induced by puromycin, and was localized to podocytes. In conclusion, TWEAK activates the non-canonical NF kappa B pathway in podocytes, leading to upregulation of CCL21 expression. The non-canonical NF kappa B pathway should be explored as a potential therapeutic target in proteinuric kidney disease.

It is well documented that inflammatory chemokines play a significant role in the development of multiple sclerosis (MS) and its model, experimental autoimmune encephalomyelitis (EAE). Recently, the involvement of homeostatic (or lymphoid) chemokines in the pathogenesis of autoimmune diseases has become an object of intensive study. In this work, quantitative analysis of CCL19, CCL21 and CCR7 expression in the central nervous system (CNS), as well as in inflammatory mononuclear cells isolated from several organs during the first attack, remission and the second attack of chronic-relapsing EAE (ChREAE), was performed. Using real-time PCR, RNAse Protection Assay and immunohistochemistry, the expression of both chemokines, as well as of their common receptor CCR7, was analyzed in the brain, spleen, lymph nodes and peripheral blood mononuclear cells. Increased expression of CCL19 and CCL21 was observed mostly in mononuclear inflammatory cells isolated from the CNS during active ChREAE. At the same time the expression of CCR7 in blood mononuclear leukocytes was reduced. This observation extends our current knowledge about the possible role of chemokines CCL19, CCL21 and their receptor CCR7 in the pathogenesis of ChREAE and, by extension, MS.