KLK5 induces shedding of DPP4 from circulatory Th17 cells in type 2 diabetes

Abstract

ObjectiveIncreasing plasma levels and activity of dipeptidyl peptidase-4 (DPP4 or CD26) are associated with rapid progression of metabolic syndrome to overt type 2 diabetes mellitus (T2DM). While DPP4 inhibitors are increasingly used as anti-hyperglycemic agents, the reason for the increase in plasma DPP4 activity in T2DM patients remains elusive.MethodsWe looked into the source of plasma DPP4 activity in a cohort of 135 treatment naive nonobese (BMI < 30) T2DM patients. A wide array of ex vivo, in vitro, and in silico methods were employed to study enzyme activity, gene expression, subcellular localization, protease identification, surface expression, and protein–protein interactions.ResultsWe show that circulating immune cells, particularly CD4+ T cells, served as an important source for the increase in plasma DPP4 activity in T2DM. Moreover, we found kallikrein-related peptidase 5 (KLK5) as the enzyme responsible for cleaving DPP4 from the cell surface by directly interacting with the extracellular loop. Expression and secretion of KLK5 is induced in CD4+ T cells of T2DM patients. In addition, KLK5 shed DPP4 from circulating CD4+ T helper (Th)17 cells and shed it into the plasma of T2DM patients. Similar cleavage and shedding activities were not seen in controls.ConclusionsOur study provides mechanistic insights into the molecular interaction between KLK5 and DPP4 as well as CD4+ T cell derived KLK5 mediated enzymatic cleavage of DPP4 from cell surface. Thus, our study uncovers a hitherto unknown cellular source and mechanism behind enhanced plasma DPP4 activity in T2DM.

The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin

“…Levels of both membrane-bound DPP-4 protein and plasma DPP-4 enzymatic activity are altered in several pathophysiological states, including cancer, inflammation, infections, immune disorders, type 2 diabetes, and kidney disease [28,31]. The increased levels of soluble DPP-4 in type 2 diabetes seem to be at least partly derived from proteolytic processing of membrane-bound DPP-4 by kallikrein-related peptidase 5 on circulating CD4 + T helper (Th)17 cells [40].…”

CD26 expression is attenuated by TGF‐β and SDF‐1 autocrine signaling on stromal myofibroblasts in human breast cancers

“…Shedding of membrane CD26 has been widely recognized on various cell types, such as human adipocytes, vascular smooth muscle cells (VSMCs), and peripheral blood mononuclear cells (PBMCs) . Several matrix metalloproteinases (MMPs) mediate the membrane CD26 shedding on adipocytes and VSMCs .…”

“…Several matrix metalloproteinases (MMPs) mediate the membrane CD26 shedding on adipocytes and VSMCs . Kallikrein‐related peptidase 5 (KLK5) also plays roles in the shedding of CD26 on human PBMCs; the CD26 shedding from PBMCs is significantly inhibited by treatment with a KLK5 inhibitor, while treatment with recombinant KLK5 has the opposite effect, dramatically inducing CD26 shedding from CD4 + T cells …”

“…Shedding of membrane CD26 has been widely recognized on various cell types, such as human adipocytes, vascular smooth muscle cells (VSMCs), and peripheral blood mononuclear cells (PBMCs). 48,49 Several matrix metalloproteinases (MMPs) mediate the membrane CD26 shedding on adipocytes and VSMCs. 48 Kallikrein-related peptidase 5 (KLK5) also plays roles in the shedding of CD26 on human PBMCs; the CD26 shedding from PBMCs is significantly inhibited by treatment with a KLK5 inhibitor, while treatment with recombinant KLK5 has the opposite effect, dramatically inducing CD26 shedding from CD4 + T cells.…”

Lymphocytes are a major source of circulating soluble dipeptidyl peptidase 4

“…However, in their studies, DPP4 secretion from adipocytes and smooth cells was not impacted by brefeldin A treatment. Nargis et al recently reported an alternative mechanism whereby kallikrein-related peptidase 5 (KLK5) was shown to mediate enzymatic cleavage of DPP4 from the surface of IL-17-producing CD4 + T helper type 17 (Th17) cells [52]. Thus, the mechanism of DPP4 secretion may be tissue-dependent and additional biochemical analysis of activated lymphocytes may provide additional insights.…”