Decreased Inflammatory Response of Monocytes and Macrophages in Patients with Granulomatosis with Polyangiitis

Abstract

Background: Granulomatosis with polyangiitis (GPA), formally known as Wegners granulomatosis, is characterized by the necrotizing vasculitis involving medium and small vessels and granulomatous inflammation. Sinonasal airway of GPA patients is heavily colonized with bacteria despite extensive inflammatory infiltrates, indicating an impaired local immunity in patients with GPA. This study is aimed to investigate whether monocytes in patients with GPA are polarized towards alternative activation with a decreased immune response including tumor necrosis factor (TNF)-α production and whether the tissue infiltrating monocytes/macrophages in granulomatous GPA lesions express CD163, a marker of alternative macrophage activation.

Methods: CD16+ monocytes in peripheral blood mononuclear cells (PBMCs) from GPA patients (n=23) and health controls (n=14) were quantified by flow cytometry. Monocytes were stimulated with increasing concentrations of lipopolysaccharide (LPS), and TNFα production was measured at 4 and 24 hours using flow cytometry analysis and enzyme-linked immunosorbent assay. CD163 expression in lung biopsies of patients with GPA was detected by immunohistochemistry.

Results: Circulating CD16+ monocytes were more frequent in GPA patients compared to controls (4.7 ± 2.8% vs. 1.9% ± 1.2%, P < 0.001). Upon activation with LPS, TNFα production did not differ between CD16+ and CD16- monocytes. Activated monocytes from GPA patients produced significantly less TNFα as compared with monocytes from healthy controls (2,903 ± 1,320 pg/mL vs. 8,335 ± 4,569 pg/mL, P<0.001). CD163 expression on surface of activated monocytes decreased with increased production of TNFα. Further, CD163+ macrophages were abundantly present in granulomatous lesions of GPA lungs.

Conclusions: Decreased TNFα production by circulating monocytes and CD163 overexpression by tissue monocytes/macrophages in granulomatous pulmonary lesions suggest that alternative activation of monocytes/macrophages might play an important role in GPA pathogenesis. Treatment to restore the normal monocyte differentiation might offer a new therapeutic target.