Cellular response towards inflammation


The inflammatory response results from a complex inter- play between different mediator cascades (e.g. complement, cytokines and chemokines), the inflammatory blood cells of (neutrophils, eosinophils and monocytes) that are recruited to the site, and 'resident' tissue cells, particularly the micro- vascular cells of the organ or tissue involved. The beneficial nature of the inflammatory response, particularly in host defence against infection, has been recognised for centuries, as have the classical external signs: calor, rubor, dolor ure functio laesa-heat, redness, pain and loss of function. However, it has only comparatively recently become clear that these identical processes may, under circumstances that are not fully understood, be centrally involved in the patho genesis of a wide range of common and important diseases (see the information box). The acute inflammatory response is often restricted to recruitment of neutrophil granulocytes and inflammatory macrophages yet its effectiveness is clearly exemplified in streptococcal lobar pneumonia . In more complex situations (e.g. some viral diseases), a chronic inflammatory response causes additional local recruitment of lymphocytes, sometimes leading to a fibrotic response, or against some parasites (e.g. in schistosomiasis) there may be local recruitment of large numbers of eosinophil granulocytes in addition to neutrophils and lymphocytes, thus completing the cellular picture typical or allergic inflammation. Defects in the cellular or mediator components of inflammation can lead to major problems host defence against bacterial infections. These can inherited (e.g. leucocyte adhesion deficiency-LAD- see the information box) or acquired (e.g. drug-induced neutropenia.)

Inherited defect of B2, integrins on the neutrophil surface
Clinical features
  • Destructive skin ulceration without pus formation (no neutrophil emigration)
  • Chronic neutrophilia
  • Poor wound-healing with dystrophic scars
  • Delayed umbilical cord separation in the neonate
  • Recurrent septicaemia and life-threatening infections

with rare inherited abnormalities in neutrophil granules. Most of these are characterised by repeated bacterial infections. Chronic granulomatous disease due to a defect in NADPH oxidase is perhaps the best-recognised example.

The macrophage

Resident tissue macrophages, e.g. Kupffer cells in the liver, alveolar macrophages in the lung, mesangial cells in the kidney, microglial cells in the brain and resident macrophages in the peritoneum and lymph nodes, derive from circulating monocytes which originate in the bone marrow. Tissue macrophages have a number of important functions (see the information box) and via a range of surface receptors are able to respond in different ways to a wide range of external stimuli. Like neutrophils, resident macrophages can ingest and kill bacteria, but perhaps their major role in acute inflammation is to initiate and orchestrate the inflammatory response by the secretion of important cytokines

Constituents of human neutrophil granules
Azurophil granules Specific granules
Microbicidal enzymes Lysozyme Myeloperoxidase Collagenase
Neutral proteinases Elastase Collagenases Cathepsin G Collagenases
Acid hydrolases Phosphatases Lipases Sulphatases Histonase Cathepsin D B glycerophosphatase Esterase Neuraminidase 5' nucleotidase Phosphatases
Others protein Defensins Cationic proteins Glycosaminoglycans Chondroitin sulphate Lactoferrin Vitamin B12 binding protein C3bi receptor Cytochrome B Flavoproteins

and chemokines. For example, they can secrete large quantities of the neutrophil chemokine IL-8 and other chemokines that specifically attract monocytes to the inflamed site. These monocytes rapidly mature into inflammatory macrophages, which have huge phagocytic and bacterial killing capacity and which also have

Inflammatory response
  • Initiation
  • Generation of neutrophil chemokines (e.g. IL-8)
  • Generation of monocyte chemokines (e.g. MIP-1a)
  • Generation of agents (IL-1, TNF-a) that activate endothelial cells
  • Generation of acute phase response (IL-1, TNF, IL-6)
  • Amplification
  • Secretion of agents that stimulate bone marrow
  • generation of leucocytes (IL-1, TNF-a)
  • Resolution
  • Scavenging of necrotic and apoptotic cells and debris
  • Repair/fibrosis
  • Remodelling-elastase, collagenase
  • Scar formation-IL-1, platelet-derived growth factor
  • (PDGF), fibroblast growth factor (FGF)
Immune response
Antigen presentation—lymphocyte activation
Host defence
Phagocytosis and killing of microorganisms by oxygen radicals, nitric oxide-dependent mechanisms and enzymes
Antitumour effects
Lysis of tumour cells by TNF-a and nitric oxide-dependent mechanisms

important scavenging function for damaged microorganisms and proteins and for aged and damaged host cells in the 'clearing up' processes during the resolution of the inflammatory response. Finally, resident and inflammatory macrophages can secrete a range of cytokines that are responsible for tissue repair processes, but clearly in

  • Fibrosing alveolitis
  • Chronic bronchitis and emphysema
  • Chronic pyelonephritis
  • Atherogenesis
  • Rheumatoid arthritis
  • Psoriasis
  • Multiple sclerosis
Acute inflammatory tissue injury (neutrophil dominant)
  • Acute respiratory distress syndrome (ARDS)
  • Acute gout
  • Myocardial infarction/reperfusion injury
  • Acute glomerulonephritis
Chronic inflammation (lymphocyte/macrophage dominant fibrosis)
Chronic allergic inflammation (lymphocytes and eosinophil dominant)
  • Bronchial asthma
  • Eczema

effective control of these processes may underline the excessive fibroproliferative response that characterises chronic inflammatory diseases such as pyelonephritis and fibrosing alveolitis (see the information box bottom left).

The eosinophil granulocyte

Like the neutrophil, the eosinophil is a bone marrow, derived, blood-borne polymorphonuclear leucocyte, but unlike the neutrophil its cytoplasm stains pink on haemotoxylin/ eosin staining, and electron microscopy , shows the large angular granules that characterise this cell. Eosinophils appear to be selectively attracted to tissue as the result of specific chemotaxins (e.g. IL-5 and the chemokines RANTES and eotaxin that are secreted by macrophages and T lymphocytes). Most of the granule contents are common to the neutrophil, although som agents, e.g. eosinophil peroxidase (EPO) and major basic protein (MBP), are specific for the eosinophil. Eosinophils have probably evolved to aid human host defences against parasites such as schistosomes and worms , but they are also implicated in allergic diseases such as asthma.

THE ACUTE INFLAMMATORY RESPONSE In a classical acute anti-inflammatory response, such as occurs as a result of streptococcal invasion of the lung airspaces in the evolution of lobar streptococcal pneumonia , a stereotyped sequence of cellular and mediator events is usually provoked
  • Neutrophils sequester in the local lung capillaries, emigrate through the vascular endothelium, the basement membrane and the alveolar epithelial layer, and begin to appear in the alveolar spaces within 2 hours, with a peak of emigration at 4-6 hours.
  • Neutrophils become activated, phagocytose and destroy opsonised bacteria by secreting reactive oxygen species (ROS) and granule enzymes into the phagosome.
  • Monocytes begin to emigrate from capillaries into tissues at about 6 hours, reaching a peak at 18-24 hours. Monocytes rapidly mature into inflammatory macrophages which kill and scavenge dead organisms and debris.

In most inflammatory reactions there is vascular dilatation and leakage of fluid and proteins during the early stage of neutrophil emigration. This exudate contains an array of proteins and other mediators, e.g. members of the complement and coagulation cascades, immunoglobulins and other factors that may aid host defence and later repair. In a 'successful! beneficial inflammatory response, such as occurs in most cases of lobar pneumonia, the inflammatory cells rapidly disappear as the lesion resolves. It is likely that extravasated granulocytes undergo apoptosis locally and are phagocytosed by macrophages; tissue numbers of macrophages then return to normal. Even in 'beneficial inflammation' like lobar pneumonia, there is often bystander' injury to local endothelial cells and epithelial cells; these must be repaired/ replaced before tissue homeostasis is re-established.

Much has been learned about the cellular and mediator events involved in the initiation of acute inflammation; some of these mechanisms may provide new targets for therapy in inflammatory disease. Local tissue perturbation, e.g. bacterial invasion, causes the release of inflammatory mediators. Some of these act as chemotaxins, attracting neutrophils then monocytes to the site; others (e.g. TNF-O., IL-1) act on local vascular endothelial cells to promote their

Important receptors in leucocyte-endothelial adhesion and transmigration
Family Receptor Distribution Ligand/counter-receptor Promotes adhesion to
Integrin family LFA-1 (CD11a/CD18) All leucocytes ICAM-1, ICAM-2, ICAM-3 Endothelial cells
MAC-1/CR3 (CD11b/CD18) Granulocytes Monocytes Lymphocytes ICAM-1, C3bi, factor X Endothelial cells Opsonised particles
P150.95 (CD11c/CD18) Granulocytes Monocytes ? Endothelial cells
Selectin family L-selectin (CD) Neutrophils Monocytes Lymphocytes ? Endothelial cells
P-selectin (CD62) Endothelium Sialyl Lewis X (CD15) Neutrophils
Immunoglobulin superfamily ICAM-1 (CD54) Endothelium Epithelium LFA-1 (CD11a/CD18) MAC-1 (CD11b/CD18) All leucocytes
ICAM-2 Monocytes Lymphocytes Endothelium LFA-1 (CD11a/CD18) All leucocytes
VCAM-1 Activated endothelium VLA-4 Monocytes Eosinophils

adhesion to the surface of activated inflammatory cells . Bacteria can generate neutrophil chemotaxins in several ways; some of their own products (e.g. formylated peptides) are chemotactic, activation of the complement system will generate C5a, an important neutrophil chemotaxin; but perhaps the most important mechanism is the induction of chemokine generation by resident macrophages and other tissue cells. The chemokines (e.g. IL8, RANTES and eotaxin) are a large family of small, but potent, peptides which attract and activate different inflammatory cells via specific surface receptors. The arrest of neutrophils in local microvessels is a necessary prelude to their transmigration through the endothelial and epithelial layers and it involves a two-step process. The first phase is one of transient adhesion which is mediated by adhesion molecules of the selectin family; the second phase of tight adhesion and transmigration is mediated by adhesion molecules of the integrin family . It is now clear that just as there are many neutrophil chemotaxins, there are also many adhesion molecules that can mediate neutrophil adhesion to microvascular endothelial cells. The importance of the integrin mechanism in host defence is well illustrated by LAD , which is caused by an inherited defect in the ß chain of the leucocyte integrins.

Although eosinophils and monocytes sequester and emigrate by very similar mechanisms, it is likely that selective accumulation is achieved by differential secretion and expression of the different members of the chemokine and adhesion molecule repertoire (e.g. IL-8 is chemotactic specifically for neutrophils, whereas RANTES and eotaxin specifically attract eosinophils).


While streptococcal pneumonia exemplifies an acute inflammatory response in which the recruited cells are virtually restricted to neutrophil granulocytes and cells of the monocyte/macrophage lineage, in other situations, e.g. some viral infections, large numbers of lymphocytes are recruited. This more persistent tissue picture results from a combination of the inflammatory and classical immune responses. The further recruitment of eosinophils in a chronic inflammatory response is a feature of allergic inflammation, e.g. in filariasis and schistosomiasis.

However, these patterns of cellular responses can also be “turned against us' in various diseases if they occur inan. propriately or in an uncontrolled fashion. For example, an excessive or inappropriate acute inflammatory response is responsible for many acute tissue injury syndromes, acute gout and acute glomerulonephritis . A chronic inflammatory response and chronic tissue destruction or an excessive fibrogenic response are key features of rheumatoid arthritis , chronic pyelonephritis , fibrosing alveolitis and chronic bronchitis and emphysema. An allergic inflammatory response characterises asthma and eczema . The vast redundancy of mechanisms displayed in various aspects of the inflammatory response may be advantageous in antibacterial host defence but it poses problems for the development of specific therapy inflammatory diseases.

The fundamental molecular machinery of the cell
The cell from birth to death
Interactions of the cell with its local environment
Inflammation: an orchestrated cellular response
Organisation and function of the immune system
Genetics and disease
Investigation of the molecular basis of disease
Types of genetic disease