Differential Membrane Expression of Toll-Like Receptors and Intracellular Cytokine Induction in Peripheral Blood Monocytes of Patients with Chronic Kidney Disease and Diabetic Nephropathy

Abstract

Background: Toll-like receptors (TLRs) are key players in the innate immune system whose activation leads to an inflammatory response. Inflammation plays an important role in the pathogenesis of chronic kidney disease (CKD) and diabetes mellitus. The aim of our study was to assess the proinflammatory state of nondialysis CKD patients by evaluating the membrane expression of TLR2 and TLR4 and the intracellular IL-1β and IL-6 production in response to the ligand Pam3Cys-Ser-(Lys)4 (Pam3CSK4). Methods: 85 nondialysis CKD patients [mean estimated glomerular filtration rate: 34 (17-90) ml/min/1.73 m²] were divided in 2 groups: 55 nondiabetic CKD patients (CKD group) and 30 patients with diabetic nephropathy (DN group). The two groups were compared with 36 healthy subjects (control group). TLR2 and TLR4 membrane expression in monocytes and Pam3CSK4-induced intracellular production of IL-1β and IL-6 were assessed by flow cytometry. Results: Both patient groups showed increased TLR2 membrane expression compared with the control group, both at baseline (p < 0.05 for both) and after Pam3CSK4 stimulation (p < 0.05 for both). The DN group exhibited significantly higher TLR4 expression at baseline compared to the CKD and control groups (p < 0.04 and p < 0.02, respectively). Intracellular IL-1β and IL-6 levels at baseline were significantly lower in CKD patients compared to the DN and control groups. After Pam3CSK4 stimulation, intracellular IL-1β and IL-6 increased in all groups, but were lower in the CKD group versus the control group or DN group, which exhibited higher levels than the controls. Conclusions: NondialysisCKD patients showed significant alterations in TLR2 and TLR4 membrane expression, and impaired Pam3CSK4-induced cytokine production in monocytes, a phenomenon that is markedly influenced by the presence of diabetes.

Chronic Kidney Disease Is Characterized by Expansion of a Distinct Proinflammatory Intermediate Monocyte Subtype and by Increased Monocyte Adhesion to Endothelial Cells

“…45,46 Zikou et al provided evidence that the effect of CKD on monocyte cytokine production may depend on CKD etiology with monocyte responses increased in diabetic kidney disease and attenuated in other CKD etiologies. 47 Variations in the isolation procedure, experimental technique, and severity of CKD studied may partially explain these discrepant results. Our data suggest that monocyte capacity to produce TNF and IL-1 β , including the rapid and intense response of HLA-DR hi IMs, is preserved—neither increased nor suppressed—in stable non–dialysis-dependent CKD.…”

Toll-like receptor 4 and the inflammation during aging

“…However, it has been hypothesized that TLR4 may be introduced as an important PRR involved in the induction of inflammation in the elderly population, because the antagonists of TLR4 can inhibit the interaction of ligands with TLR4 and block its intracellular signaling and decreased inflammation during aging 11 . Additionally, it has been proven that several aging complications like type 2 diabetes, cardiovascular diseases and kidney diseases have a potential link with TLR4 and its intracellular signaling molecules, which play an important role in the pathogenesis of the human diseases [12][13][14][15][16] . Thus, it seems that TLR4 can play key roles during aging inflammation.…”

Toll-like receptor 2 agonist exacerbates renal injury in diabetic mice

“…TLR2 and/or TLR4 are actively involved in the development of kidney diseases, such as ischemia-reperfusion injury, cisplatin-induced nephrotoxicity and crescentic glomerulonephritis (11–13). TLR2 and/or TLR4 are also required for the development of DN (14–18). In streptozotocin (STZ)-induced diabetic animal models, TLR2 and TLR4 expression is enhanced, accompanied by the activation of their downstream signaling pathways (14–16).…”

“…In streptozotocin (STZ)-induced diabetic animal models, TLR2 and TLR4 expression is enhanced, accompanied by the activation of their downstream signaling pathways (14–16). Clinical studies have indicated that TLR2 and TLR4 expression and activity are significantly upregulated in diabetic patients (17,18), indicating that TLR2 and/or TLR4 may represent targets for the prevention of DN. Previous reports showed that TLR2 primarily signals through the MyD88-dependent pathway to induce inflammation (14).…”