Current Concepts of Hyperinflammation in Chronic Granulomatous Disease
Impaired apoptosis/efferocytosis underlying hyperinflammation in CGD. Apoptotic cells (here shown for neutrophils, PMN) externalize phosphatidylserine (PS), which is recognized through PS-receptors on macrophages. This interaction enables the uptake of apoptotic cells by macrophages, a process termed “efferocytosis”. Successful efferocytosis leads to the secretion of the anti-inflammatory cytokine TGF-β by macrophages and thereby facilitates resolution of acute inflammation. Due to an impaired externalization of PS by CGD neutrophils and/or other neutrophil-macrophage interaction mechanisms, both apoptosis and efferocytosis have been described to be dysfunctional in CGD. This leads to unbalanced neutrophil necrosis with release of intracellular proteases/oxidants and persistence of (sterile) inflammation. Two pathways have recently been proposed to be involved in this impairment: PS/PSR interactions were found to trigger downstream pathways comprising IL-4 and PPARγ, which are critically involved in the regulation of efferocytosis. Beyond that, impaired phagocytosis of apoptotic cells by CGD macrophages could be reversed by IFN-γ treatment, an effect that was mediated through NO production, endogenous TNF-α production, and Rac activation.
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