Deficiency of p67^phox, p47^phox or gp91^phox in chronic granulomatous disease does not impair leucocyte chemotaxis or motility

Abstract

Summary. Chronic granulomatous disease (CGD) is a syndrome characterized by failure of the NADPH oxidase of phagocytes that generates superoxide, which is central to the microbicidal process. Cytosolic components of this oxidase system include the proteins p67 phox and p47 phox , deficiencies of which cause the autosomal recessive form of CGD, whereas the X-linked form of the disease is characterized by a deficiency in the plasma membrane component gp91 phox . Components of the oxidase system have been reported to be associated with the cytoskeleton and neutrophils from CGD patients have been reported to have a defective chemotactic response in Boyden chambers. Using a chamber that permits the direct observation of cell behaviour in a linear gradient of a chemoattractant, we have analysed the chemotactic response of neutrophils from a patient lacking p67 phox ; from another lacking p47 phox and from a third lacking gp91 phox . The results of measuring the speeds and directions of locomotion of the cells show that their speeds are undiminished relative to cells from healthy control subjects and that their directions of migration are at least as strongly biased in the direction of the gradient as those of the control cells. We conclude that these definitive aspects of the chemotactic response are not abnormal in either the autosomal recessive or the X-linked forms of CGD and that they are therefore not factors in the predisposition to infection that characterizes the syndrome.

A Role for Cdc42 in Macrophage Chemotaxis

“…Chemotaxis was assessed by direct observation and recording of cell behavior in stable concentration gradients of CSF-1 using the Dunn chemotaxis chamber (Weber Scientific International Ltd., Teddington, UK). This apparatus permits the directions of migration of individual cells to be measured in relation to the direction of the gradient and the time course of the response to be followed ( Zicha et al, 1991 , 1997 b ). Details of the construction and calibration of the apparatus are given in Zicha et al (1991) and Webb et al (1996) .…”

Oxidant Sensing by TRPM2 Inhibits Neutrophil Migration and Mitigates Inflammation

“…In addition, studies have demonstrated that mice lacking the p47 phox or gp91 phox subunits of NADPH oxidase exhibit higher neutrophil infiltration levels than WT mice (Gao et al, 2002; Pollock et al, 1995). However, directional neutrophil migration is either unaffected or reduced when ROS generation by neutrophils is inhibited (Hattori et al, 2010; Zicha et al, 1997). Thus, while neutrophil-generated ROS can regulate neutrophil migration, the underlying signaling mechanisms and ROS substrates that mediate neutrophil migration in response to chemoattractants have not been identified.…”

Characterization of Nitric Oxide Consumption Pathways by Normal, Chronic Granulomatous Disease and Myeloperoxidase-Deficient Human Neutrophils

“…Therefore, the inability of CGD leukocytes to metabolize NO may render them more sensitive to its inhibitory effects. In vitro studies under NO-free conditions show that chemotaxis of neutrophils from CGD patients does not differ from healthy controls (60). However, decreased leukocyte adhesion and emigration in cholesterol-fed p47 phoxϪ/Ϫ mice and delayed monocyte or T cell migration into livers of Leishmania donovanii-infected gp91 phoxϪ/Ϫ mice indicate that lack of NADPH oxidase renders leukocytes less able to migrate during inflammation in vivo (6,7).…”