Diminished production of anti-inflammatory mediators during neutrophil apoptosis and macrophage phagocytosis in chronic granulomatous disease (CGD)

Abstract

Genetic defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme system result in chronic granulomatous disease (CGD). In addition to recurrent, life-threatening infections, patients with CGD frequently present with sterile inflammatory complications, suggesting that NADPH-oxidase deficiency predisposes to these responses in the absence of persistent microbial infection. The mechanisms involved in the aberrant, inflammatory process are unknown. In this study, we have shown that neutrophils isolated from CGD patients, which are more resistant to spontaneous apoptosis in vitro, also produce significantly less of the anti-inflammatory mediator cyclopentenone prostaglandin D(2) (PGD(2)). In addition, during phagocytosis of opsonized and nonopsonized apoptotic targets, CGD macrophages are severely compromised in their ability to produce PGD(2) and transforming growth factor-beta (TGF-beta). We suggest that delayed apoptosis of inflammatory cells, such as neutrophils and deficient production of the anti-inflammatory mediators PGD(2) and TGF-beta during macrophage clearance of apoptotic debris and invading pathogens, contributes to persistence of inflammation in CGD.

Rescuing of deficient killing and phagocytic activities of macrophages derived from non-obese diabetic mice by treatment with geldanamycin or heat shock: potential clinical implications

“…Moreover, in Mfs derived from NOD mice, it has been reported that, together with the impaired phagocytosis of AC (O'Brien et al 2006), an abnormal production of IL-12 (Rainbow et al 2008), IL-21 (King et al 2004), and IL-1β (Bouma et al 2005) also occurs. It is important to remark that quantitative and kinetic balance of pro-and antiinflammatory mediators contributes to restoring immunological homeostasis and determines the final outcome of biological processes (Brown et al 2003). Thus, we investigated potential alterations in cytokine production by NOD Mfs in response to pro-inflammatory stimuli such as bacteria particles or lipopolysaccharide (LPS).…”

Reactive Oxygen Species Regulate Neutrophil Recruitment and Survival in Pneumococcal Pneumonia

“…Delayed constitutive and Fas-mediated apoptosis occurs in neutrophils from patients with CGD (37). Decreased levels of apoptosis of neutrophils from patients with CGD are associated with decreased production of antiinflammatory mediators prostaglandin D 2 and transforming growth factor-b (38). Thus, inhibition of apoptosis has indirect effects mediated by downstream cytokines/chemokines.…”

Cutaneous and other lupus-like symptoms in carriers of X-linked chronic granulomatous disease: incidence and autoimmune serology

“…Data on protein levels or activity of the classical complement pathway are not available in our group of carrier mothers. However, both the process of apoptosis and clearance of apoptotic cells are impaired in patients with X-CGD with impaired expression of phosphatidyl serine, which is crucial for apoptotic cell clearance, and impaired production of prostaglandin D2 and transforming growth factor b, both potent anti-inflammatory agents, during the phagocytosis of opsonized and nonopsonized apoptotic targets [24,25]. Together this suggests that in X-CGD damaged cells undergo abnormal apoptosis, are poorly cleared by the reticuloendothelial system and the normal anti-inflammatory response is impaired.…”