Current concepts of hyperinflammation in chronic granulomatous disease

Abstract

Chronic granulomatous disease (CGD) is the most common inherited disorder of phagocytic functions, caused by genetic defects in the leukocyte nicotinamide dinucleotide phosphate (NADPH) oxidase. Consequently, CGD phagocytes are impaired in destroying phagocytosed microorganisms, rendering the patients susceptible to bacterial and fungal infections. Besides this immunodeficiency, CGD patients suffer from various autoinflammatory symptoms, such as granuloma formation in the skin or urinary tract and Crohn-like colitis. Owing to improved antimicrobial treatment strategies, the majority of CGD patients reaches adulthood, yet the autoinflammatory manifestations become more prominent by lack of causative treatment options. The underlying pathomechanisms driving hyperinflammatory reactions in CGD are poorly understood, but recent studies implicate reduced neutrophil apoptosis and efferocytosis, dysbalanced innate immune receptors, altered T-cell surface redox levels, induction of Th17 cells, the enzyme indolamine-2,3-dioxygenase (IDO), impaired Nrf2 activity, and inflammasome activation. Here we discuss immunological mechanisms of hyperinflammation and their potential therapeutic implications in CGD.

Figure 1

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.

Figure 2

Other recently proposed mechanisms of hyperinflammation in CGD. Three independent mechanisms leading to hyperinflammation with increased numbers of Th17 cells have been recently proposed in CGD: Reduced IDO and Nrf2 activity and increased NLRP3 activation.