Karen Bedard and Karl-Heinz Krause

urst is also found at high levels in eosinophil granulocytes
(792, 965). There are also some limited indications
about a NOX-type enzyme in basophils and mast cells
(852). To our knowledge, no expression of NOX isoforms
other than NOX2 has been reported in granulocytes. The
function of NOX2 in neutrophils is mainly host defense.
The situation might be similar for eosinophils, which are
involved in the host defense against metazoan parasites,
while in basophils and mast cells, a regulation of cellular
responses by NOX-derived ROS has been suggested (852).
Increased generation of ROS by NOX2 from granulocytes
has been implicated in a large number of inflammatory
disease (for review, see Refs. 44, 157, 245, 652, 752, 796).
From a clinical perspective, the most widely studied
NOX2-related neutrophil disease is CGD, a syndrome that
can be caused by genetic deficiency of NOX2, p47 phox ,
p67 phox ,orp22 phox . The relatively rare disease is characterized
by an enhanced sensitivity to bacterial and fungal
infections (384, 801). Many aspects of the disease phenotype
could be reproduced in NOX2- and p47 phox -deficient
mice (421, 709). CGD and its mouse models are also
characterized by increased inflammation in response to
noninfectious material (see sect. IIIA5).
3. Macrophages
Macrophages are tissue-localized phagocytes derived
from circulating monocytes. Many tissues have particular
types of macrophages with specific features and function,
including microglia in the CNS, osteoclasts in the bone,
and Kupffer cells in the liver. Particularities of tissuespecific
macrophages are discussed in the respective sections.
The topic of the NOX expression in macrophages
(see, for example, Ref. 269) cannot be covered in detail in
this review. We will only briefly summarize some relevant
aspects with respect to the NOX family.
It appears that all types of macrophages express the
phagocyte NADPH oxidase NOX2 and its subunits
p47 phox , p67 phox , p40 phox , and p22 phox . However, as opposed
to granulocytes, there are indications that macrophages
may also express other types of NOX. Osteoclasts
express NOX4 (969, 973). Kupffer cells have even been
suggested to express several NOX isoforms in addition to
NOX2 (739).
Obviously one of the key functions of NOX2 in macrophages
is killing of phagocytosed microorganisms, as
described before for neutrophil granulocytes. However,
the situation in macrophages is more complex than in
granulocytes. In addition to killing, NOX enzymes in macrophages
and macrophage-related cells are likely to be of
importance in activation of kinases and transcription factors,
gene expression (in particular proinflammatory
genes), regulation of proliferation, and apoptosis (59, 96,
269, 753, 754).
THE NOX FAMILY OF ROS-GENERATING NADPH OXIDASES 285
4. Dendritic cells
Dendritic cells are antigen-presenting cells of myeloid
origin. Dendritic cells express NOX2 and its subunits,
even though the phagocyte respiratory burst declines
during differentiation of monocytes towards dendritic
cells (979). Preincubation with proinflammatory
ligands or pathogen-derived molecules leads to an activation
of the phagocyte NADPH oxidase NOX2 in dendritic
cells (248, 925). Whether NOX2 in dendritic cells plays a
role in bacterial killing is debated (248, 785, 925). However,
NOX2 plays an important role in the presentation of
antigens, more specifically in the so-called cross-presentation.
For cross-presentation, proteins must be partially
degraded in the phagosome, followed by 1) translocation
to the cytosol, 2) further degradation, 3) transport into
the ER, 4) loading to major histocompatibility complex
class I (MHC I), and finally 5) presentation to CD8 � T
cells. NOX2 is involved in the initial degradation of proteins
in the phagosome. It regulates this process through
alkalinization of the phagosome, which limits the activity
of lysosomal proteases. Dendritic cells lacking NOX2
show enhanced phagosomal acidification and therefore
overshooting antigen degradation, which destroys potential
peptides for T-cell recognition (785).
Thus NOX2 is at the center of the function of dendritic
cells, namely, the regulation of antigen presentation.
5. B lymphocytes
Physiol Rev VOL 87 JANUARY 2007 www.prv.org
B lymphocytes, including EBV-transformed B cells, B
cell lines, tonsillar B lymphocytes, and peripheral B cells,
generate ROS (431, 471, 472, 573, 574, 814, 922). At least
for EBV-transformed B cells and lymphomas, it is convincingly
documented that the ROS generation occurs
through the phagocyte NADPH oxidase NOX2 (431, 472,
573, 814, 922). B cells within lymphoid tissues are also
likely to express NOX5 (56). The relative contribution of
NOX2 and NOX5 to B-cell ROS generation and whether
additional NOX isoforms are also of relevance is presently
unknown. The discovery of NOX2-dependent ROS generation
by EBV-transformed B cells is of particular importance
for several reasons. First, it is a lymphocyte system
where phagocyte contamination as the source of NADPH
oxidase can be excluded. Second, it allows the establishment
of cell lines from patients. These can subsequently
be used as model systems to study genetic diseases, including
CGD (711), but also other diseases where NOX2dependent
oxidative stress might play a role (656). Third,
it allows experiments on NOX2 function requiring prolonged
cell culture and genetic manipulations, which is
impossible with neutrophils (222). And fourth, it provides
a model for studying gene transfer for correction of CGD
(138, 167, 878). Possible functions of NOX enzymes in B
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