Toll-like receptor TLR2 and TLR9 ligation triggers neutrophil activation in granulomatosis with polyangiitis.

OBJECTIVE: The aim of the study was to characterize the expression of TLR2, TLR4 and TLR9 in PMNs of patients with granulomatosis with polyangiitis (GPA) and to elucidate the role of these receptors in GPA with respect to neutrophil activation. METHODS: The expression of TLR2, TLR4 and TLR9 was determined on ex vivo PMNs in whole blood samples of GPA patients (n = 35) and healthy controls (HCs) (n = 24). Isolated PMNs were stimulated in vitro with TLR agonists and assessed for degranulation, membrane proteinase 3 (mPR3) expression, soluble l-selectin shedding and cytokine production (IL-8) in five GPA patients and five HCs. The priming effects of TLR2 and TLR9 ligation were assessed by measurement of serine protease activity after stimulation with PR3-ANCA. RESULTS: There were no significant differences in the ex vivo expression of TLRs on PMNs in HCs and GPA patients. Stimulation of TLR4 and TLR9 induced MPO release, stimulation with TLR2, TLR4 and TLR9 ligands elicited IL-8 production and stimulation of TLR2 and TLR9 led to an upregulation in mPR3 expression on PMNs with no significant differences between GPA and HC after 1 or 24 h stimulation. Priming of PMNs with TLR2 and TLR9 ligands induced degranulation after subsequent stimulation with PR3-ANCA, which was comparable to priming with TNF-α. CONCLUSION: Expression of TLR2, TLR4 and TLR9 in PMNs and the TLR-induced activation of PMNs was comparable in GPA and HC. mPR3 upregulation by TLR2 and TLR9 stimulation and the priming effect of TLR ligands on PMNs may have a potential implication for triggering disease activity during infection in GPA.

Evaluation of Aerobic Exercise Intensity in Patients with Coronary Artery Disease and Type 2 Diabetes Mellitus.

(1) Background: Physical activity is recommended in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) to reduce hyperglycemia and cardiovascular risk. Effective aerobic exercise intensity, however, is not well defined. (2) Methods: 60 consecutive patients performed cardiopulmonary exercise testing (CPX) of 30 min duration targeting a respiratory exchange ratio (RER) between 0.85 and 0.95, being strictly aerobic. Plasma glucose (PG) was measured before and after CPX as well as one and two h after exercise. Maximum exercise intensity was evaluated using a standard bicycle exercise test. (3) Results: 50 patients completed the protocol (62 ± 10 years, BMI (body mass index) 30.5 ± 4.9 kg/m2, HbA1c (glycated haemoglobin) 6.9 ± 0.8%, left ventricular ejection fraction 55 ± 8%). Aerobic exercise capacity averaged at 32 ± 21 Watt (range 4-76 Watt) representing 29.8% of the maximum exercise intensity reached. PG before and after CPX was 9.3 ± 2.2 and 7.6 ± 1.7 mmol/L, respectively (p < 0.0001). PG was further decreased significantly at one and two h after exercise to 7.5 ± 1.6 mmol/L and 6.0 ± 1.0 mmol/L, respectively (p < 0.0001 for both as compared to PG before CPX). (4) Conclusions: Aerobic exercise capacity is very low in patients with CAD and T2DM. Exercise at aerobic intensity allowed for significant reduction of plasma glucose. Individual and effective aerobic exercise prescription is possible by CPX.