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extracellular traps of neutrophils and mast cells is now thought to be central to the pathogenesis of

psoriasis. In systemic lupus erythematosus (SLE), an imbalance between NET formation and clearance

may underlie the systemic tissue damage that occurs. In fact, decreased NET degradation correlates with

renal disease. NETs may also activate complement, thereby amplifying the disease. Furthermore, the

neutrophils from patients with various autoimmune diseases appear more prone to NETose.45–47

NETs may also serve as a link between inflammation and thrombosis. They can provide a stimulus

and scaffold for thrombus formation by promoting platelet and RBC adhesion and by concentrating

effector proteins and coagulation factors. Activated endothelium produces compounds that, upon contact

with neutrophils, stimulate NETosis, which in turn, promotes endothelial damage.45–47

Regulation of Neutrophil Activity

In addition to the previously described mechanisms for controlling the inflammatory response of

neutrophils, there is substantial evidence supporting the role of apoptosis in halting and resolving the

neutrophil-derived inflammation (Box A).48 Within 90 minutes of phagocytosis, over 250 genes are

induced, of which more than 30 encode proteins integral to at least three distinct apoptotic pathways.48

These observations suggest that the mechanism inducing apoptosis is initiated quite proximal in the

inflammatory cascade, in fact, just subsequent to phagocytosis. The timely execution of a controlled cell

death program in human PMNs is essential for preventing damage to healthy tissues and for the

resolution of infection. Furthermore, evidence suggests that the phenotype of other immune cells,

including monocytes and macrophages, is altered after encountering and phagocytosing apoptotic

neutrophils. Thus, apoptotic neutrophil particles may function to downregulate the inflammatory

function of neighboring cells. In some circumstances of infection or trauma, neutrophil apoptosis may

be delayed, which might contribute to prolonged or a failure to resolve inflammation.

The inflammatory capacity of neutrophils is also transcriptionally regulated. Genes encoding

proinflammatory mediators or signal transduction molecules such as receptors for IL-8, IL-10, IL-13 are

downregulated early after activation and decrease rapidly after the initiation of apoptosis.48 In addition,

regulating oxidative stress and ROS achieve high priority as the genes involved in glutathione and

thioredoxin metabolism and heme catabolism are upregulated as is the production of reduced

glutathione.48 Hence, activation-induced apoptosis in neutrophils stimulates self-directed regulation, an

event that likely facilitates removal of neutrophils by macrophages. As aforementioned, removal of

apoptotic neutrophils by activated macrophages also appears to serve a role in modifying their function

and halting the inflammatory response.

Mononuclear Phagocytes

Monocytes circulate for about 1 to 2 days, whereafter, they constitutively hone to a particular tissue

(i.e., lung, peritoneum) to differentiate into macrophages possessing a phenotype specific to the

resident tissue (dendritic cells [DCs] of the skin, kupffer cells of the liver) (Table 7-1).4,49,50 Resident

macrophages are typically found at interfaces with blood (liver and spleen) and with lymph, where they

can readily detect, ingest, and destroy invading organisms.39 Mononuclear cells function as antigenpresenting cells (APC) in T cell–mediated adaptive immune responses, presenting antigen in the

appropriate context to effector T cells. They provide service integral to both innate and adaptive

immune responses. Evidence also supports their role in providing an “alarm” both locally and

systemically through the release of intracellular proteins (i.e., high-mobility group box 1 [HMGB1])

expressing DAMP that can function as a danger signal (see below).

Recruitment

Monocytes are recruited and emigrate to foci of inflammation utilizing similar mechanisms of adhesion

and diapedesis as described for neutrophils (Fig. 7-1). PAF, C5a, the CC chemokines, regulated on

activation, normal T cell–expressed and secreted (RANTES), MIP-1α, and chemokines of the membrane

cofactor protein (MCP) family are potent monocyte-macrophage chemotaxins.51,52 The selectin family of

adhesion receptors mediates the initial tethering of monocytes to endothelial cells.18 Firm adhesion to

the endothelium involves the interactions of β1 and β2

integrins on monocytes with the endothelial

adhesion molecules ICAM-1 and VCAM-1.18

Phagocytosis

Phagocytosis involves the IgG receptor (FcγR) and the receptor for the complement factor C3b.

Terminal sugar patterns on microbial surfaces also allow recognition by macrophages for nonspecific

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phagocytosis through the mannose lectin pathway.22 However, phagosomal maturation differs from that

which occurs in the neutrophil. Monocytes and macrophages have an endocytic pathway targeting the

phagosome to a lysosome.24 After endocytosis of a receptor–ligand complex, the contents of a vesicle

are targeted to an early endosome; the ligand and receptor dissociate, and the receptor is then recycled

to the cell surface.24 This early endosome undergoes a series of maturation steps in which it is acidified

(pH 5.5 to 6.0). This acidification is requisite for optimal protease and hydrolase activity involved in

pathogen killing. It may also be integral for phagosome maturation as titrating the acidity inhibits

phagosome–lysosome fusion.24 Ultimately, the endosome fuses with a lysosome, which is characterized

by its extreme acidity (pH <5.0) and elevated concentration of proteases.24 Lysosomes are the terminal

destination of phagocytosed material targeted for degradation.

After fusion, MPO released into phagosomes can react with hydrogen and halides to yield toxic

hypohalous acids, superoxide anion, hydrogen peroxide, and hydroxyl radical (Table 7-3). Macrophages

may also use peroxidase generated by adjacent neutrophils, eosinophils, and monocytes and acquired

through endocytosis to generate these ROS. In addition to supporting the inflammatory response,

macrophages also play an important immunoregulatory role in inflammation by scavenging apoptotic

neutrophils at sites of inflammation.39

Activation

IFNγ derived primarily from T cells is the primary activator of macrophages.4,50,53 Optimal macrophage

activation requires both interferon IFNγ and a sensitizing agent, both of which can be provided by

activated T lymphocytes. CD40 ligand on T cells can bind CD40 on macrophages to sensitize the cell.

Alternatively, membrane-associated TNFα or lymphotoxin from lymphocytes can activate macrophage

TNFα synthesis and thereby sensitize the macrophage to IFNγ.39 IL-10 promotes monocyte maturation

and macrophage differentiation.54 Other activators include GM-CSF, TNFα, IL-1, and LPS.

Activated monocytes and macrophages can produce approximately 100 different products, including

GM-CSF, M-CSF, G-CSF, IL-1, TNFα, G-CSF, and NO.39,55 Mononuclear phagocytes are important sources

of chemoattractants such as IL-8, PAF, and leukotriene B4

(LTB4

) that recruit neutrophils and other

leukocytes. Their release of HMGB1 and other DAMP molecules serves as an endogenous “danger”

signals to other immune cells in the local environment. These bind to various PRR to alter cell function.

However, systemic release of HMGB1 may also be causally related to mortality in such inflammatory

states as sepsis and trauma.56,57 The respiratory burst and subsequent production of toxic ROS mirrors

that of neutrophils.

Antigen Presentation

T cells recognize only those antigens associated with surface major histocompatibility complex (MHC)

molecules. MHC class I molecules are expressed on all nucleated cells, whereas MHC class II molecules

are restricted to APC. After phagocytosing pathogen, mononuclear cells process and display antigen to T

cells, and in doing so, initiate the development of the adaptive response (i.e., antibody formation).

There is evidence that the HSP receptor CD91 may also participate in this process (see below). This

processed antigen is presented on the APC cell surface in the context of MHC molecules that are

specifically recognized by T-cell receptors (TCRs) and essential for T-cell activation. CD4+ T cells, or

helper T cells (TH), recognize antigen coexpressed with MCH class II molecules and induce B-cell

differentiation into either memory or antigen-specific antibody-producing plasma cells. These TH cells

can also induce macrophage production of NO, ROS, and other inflammatory mediators. CD8+ cytotoxic

T lymphocytes (CTL) recognize antigen in the context of MHC class I molecules and induce target cell

lysis; they destroy host cells infected with intracellular pathogens or cells of malignant potential.58

Activated mononuclear phagocytes release IL-12, a potent stimulus for TH cells and the production of

inflammatory cytokines, and elaborate IL-15, the function of which mirrors that of IL-2.59,60

The three professional APC are DCs, macrophages, and B cells. DCs are a specialized APC, which

process and present antigen to naïve T cells. Monocytes stimulated with GM-CSF, IL-4, or IL-13

differentiate toward DC. Maturation of the DC requires TNFα or LPS stimulation.39 Epidermal

Langerhans cells, after encountering antigen, migrate through the lymphoid organs and differentiate

into mature DC. DC cells are particularly effective at presenting viral antigen. They present antigen in

the context of both MHC I and MHC II, and thereby induce both a TH1 and a TH2 response, respectively.

DC can also present antigens derived from apoptotic cells in the context of MHC I.61–63

Macrophages present antigenic peptides from ingested pathogens that persist in the phagosomes.

These peptides, usually of bacterial origin, are expressed in conjunction with MHC II molecules. B cells,

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