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Neutrophil – Innate Immune response. Neutrophil. Know mediators that prime and stimulate the neutrophil function Know mediators secreted by the neutrophil Understand the role of anti-proteinases in neutrophil function Know immunomodulators of neutrophils function. Neutrophil. Neutrophil

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  • Know mediators that prime and stimulate the neutrophil function
  • Know mediators secreted by the neutrophil
  • Understand the role of anti-proteinases in neutrophil function
  • Know immunomodulators of neutrophils function
  • Neutrophil
  • Granulocytes
  • Polymorphonuclear (PMNs)
  • Polymorphonuclear leukocytes (PMNLs)
  • Poly’s

Note: Your text has only 4 pages devoted to neutrophils.

Therefore your notes and these powerpoints are

your key resources on this topic.

neutrophils innate immune response
Neutrophils – innate immune response





Figure 8.21

neutrophil associated diseases
Neutrophil-associated diseases
  • Lung Adult Respiratory Distress Syndrome




Idiopathic pulmonary fibrosis

neutrophil associated diseases1
Neutrophil-associated diseases
  • Kidney Glomerulonephritis

Interstitial nephritis

  • Heart Myocardial reperfusion injury

Ischemic heart disease

  • Joint Rheumatoid arthritis


  • Systemic Scleroderma vasculitis
  • The neutrophil is specialized for the phagocytosis and destruction of micro-organisms and damaged or necrotic tissues.
neutrophils in the body
Neutrophils in the body
  • 3-6,000/mL of blood
  • ~70% of WBC
  • T1/2 = 6-7 hours in blood
  • T1/2 = 1-2 days in tissues



I. Morphology

  • An abundance of granules
  • Multi-lobed nucleus
  • Prominent cytoskeleton for locomotion and chemotactic functions

1. microfilaments

2. microtubules

3. intermediate filaments



of the neutrophil



  • Endogenous factors
    • C5a – complement fragment
    • IL-8
    • Platelet Activating Factor (PAF)
    • Leukotriene B4 (LTB4)
    • Fragments of collagen and fibrin
neutrophil chemotaxis
Neutrophil chemotaxis
  • C5a (C3a, C4a) act on specific receptors to produce similar local inflammatory responses (anaphylatoxins).
  • C5ais the most stable, has the highest specific biological activity, and acts on the best defined receptor.
  • All three induce smooth muscle contraction and increase vascular permeability.
neutrophil chemotaxis1
Neutrophil Chemotaxis
  • C5a also acts directly on neutrophils to increase their adherence to vessel walls, their migration toward sites of antigen deposition, and their ability to ingest particles.
neutrophil chemotaxis2
Neutrophil chemotaxis
  • IL-8
  • Chemokine produced by endothelial cells, macrophages, bronchial epithelial cells, fibroblasts, and keratinocytes.
  • IL-8 is a very strong chemoattractant for neutrophils and T-lymphocytes
neutrophil chemotaxis3
Neutrophil chemotaxis
  • Platelet Activating Factor (PAF)
  • PAF is a small phospholipid (MW 300-500) which causes:
    • platelet aggregation
    • increased vascular permeability
    • chemotaxis
neutrophil chemotaxis4
Neutrophil chemotaxis

II. Chemotaxis

  • Exogenous factors – bacterial products
    • N-formylated oligopeptides (FMLP)
    • Endotoxin (LPS)
neutrophil chemotaxis5
Neutrophil chemotaxis
  • The bacterial cell wall component, LPS (endotoxin), is first bound by a serum protein, lipopolysaccharide-binding protein (LBP).
  • The complex of LPS and LBP is then bound by CD14 on the surface of the neutrophil.
neutrophil chemotaxis6
Neutrophil chemotaxis
  • The interaction of CD14 with the LPS-LPB complex causes an increase in the adhesive activity of CR3 (CD11b/CD18) on neutrophils.

Transvascular Migration

of the Neutrophil

neutrophil activation
Neutrophil activation
  • Surface changes from smooth to ruffled membrane
  • Adhesion to endothelial cells
  • On surface: opsonins binding to C3b or Fc portion of Ig
  • Membrane invaginates and forms phagosome
  • Release of enzymes which mediate destruction of target material
neutrophil enzymes
Neutrophil enzymes
  • Azurophilic or Primary (blue)
    • These are the first granules formed in the developing neutrophil and peak degranulation is 90 minutes.
  • Specific or Secondary (pink)
    • These granules are formed later in the development of the neutrophil. These enzymes are released within 15 seconds after contact with the pathogen.
neutrophil enzymes1
Neutrophil enzymes

Primary Granules







Cathepsin G

Alkaline phosphatase

Proteinase 3



Phospholipases A2, C, D


neutrophil enzymes2
Neutrophil enzymes
  • Myeloperoxidase (MPO): is an abundant granular enzyme (accounts for 5% of dry weight of the neutrophil).
  • This enzyme combines hydrogen peroxide with chloride ions to form hypochlorous acid (HOCl = bleach).
neutrophil enzymes3
Neutrophil enzymes
  • Elastase: is a serine protease which specifically hydrolyzes elastin.
  • Elastin is the major component of elastic fibers which stretch in the walls of blood vessels, lungs, and ligaments.
neutrophil enzymes4
Neutrophil enzymes
  • The activity of elastase is controlled by an inhibitor termed a1-anti-trypsin.
  • Human neutrophil elastase (HNE) has been demonstrated in pathogenesis of emphysema, adult respiratory distress syndrome (ARDS), chronic bronchitis, rheumatoid arthritis, and psoriasis.
neutrophil enzymes5
Neutrophil enzymes

Secondary granules






Vitamin B12-binding protein

Cytochrome b558

fMLP receptor

CD11b/CD18, CD11c/CD18 (integrins)

Complement receptor 3 (CR3)


Plasminogen activator

neutrophil enzymes6
Neutrophil enzymes
  • Lysozyme: like MPO, is a microbicidal enzyme.
  • Lysozyme digests debris from cell walls of bacteria that have already been processed by other enzymes.
  • Another function of lysozyme is to modulate inflammation by suppressing neutrophil chemotaxis and oxidative metabolism.
neutrophil enzymes7
Neutrophil enzymes
  • Collagenase: cleaves collagen into two distinct and specific peptide fragments
  • Collagenaseis released by intact neutrophils during phagocytosis as a collagenase precursor (procollagenase) and is activated by trypsin, hypochlorous acid or rheumatoid synovial fluid.
neutrophil enzymes8
Neutrophil enzymes
  • Collagenase acts as an anticoagulant because it digests fibrinogen.
  • It is inhibited by a-1-antitrypsin and a-2-macroglobulin.
  • Some diseases associated with over abundant collagenase secretion include rheumatoid arthritis and certain diseases of the eye like ulcerated corneas.

Within 30 seconds after a neutrophil ingests a particle, it begins to secrete specific granule components into the phagosome via phagolysosomal fusion.

Within 3 minutes, azurophil granule components are discharged into the phagolysosome.


Control of the

Neutrophil Enzymes


anti proteinases
  • There are normal regulatory mechanisms for control of secreted neutrophil enzymes and control pathways to limit the enzyme action by anti-proteases.
  • These are highly important for neutralization of the enzymatic activities of the neutrophil proteases.
anti proteinases1
  • Protease inhibitors can comprise about 10% of the total protein of the blood.
  • Anti-protease activities are closely coupled to the generation of neutrophil reactive chlorinated oxidants (HOCl).
a 1 antitrypsin deficiency aatd
a-1 Antitrypsin Deficiency (AATD)
  • What is it?
  • Alpha-1 antitrypsin is a protease inhibitor (PI), genotype MM, which protects tissues from the effects of neutrophil.
  • It is mainly produced in the liver.
a 1 antitrypsin deficiency aatd1
a-1 Antitrypsin Deficiency (AATD)
  • Who does it affect?
  • Alpha-1 antitrypsin deficiency is genetic and it is passed onto children by their parents.  
  • There are at least 75 different variations, or alleles, of the gene.   Each person has two alleles and can pass one of these on to their children.
a 1 antitrypsin deficiency aatd2
a-1 Antitrypsin Deficiency (AATD)
  • Most people carry two copies of the M allele ie genotype MM.   People with AATD carry two copies of the Z allele ie genotype ZZ.
  • About 1 :  25 are MZ.  They are usually completely healthy but their partner will also have a 1 : 25 risk of being MZ.  If they have children, each child will have a 1 : 4 chance of being ZZ, so the overall risk for a child being ZZ is 1 : (25 x 25 x 4) = 1 : 2,500
a 1 antitrypsin deficiency aatd3
a-1 Antitrypsin Deficiency (AATD)
  • Alpha-1 antitrypsin deficiency is the most common genetic cause of liver disease children and of emphysema in adults.
  • It is also the most common genetic disease for which liver transplantation is undertaken in children.
  • PROTEIN-ENZYME IMBALANCE Neutrophil elastase is released during times of inflammation. This action is normally helpful and is balanced (neutralized) by the protein a-1 antitrypsin produced in the liver.
  • One cause of damage to the alveoli of the lung is that elastase is produced by neutrophil but there is a genetically lack of a-1 antitrypsin.
anti proteases



prevents degradation

of normal tissues

Then how can the neutrophil

perform its normal functions?

deactivation of anti proteases
Deactivation of anti-proteases


  • HOCl 1-protease inhibitor (1-PI), anti-leukoprotease (ALP), 2-macroglobulin (2-M), plasminogen activator inhibitor- 1 (PAI-1)


  • Elastase metalloprotease (TIMP) a1-antichymotrypsin (a1-ACT)
anti proteases1
  • Subsequent to this two staged attack on anti-proteases, the neutrophil enzymes are free to damage the bacterial targets, necrotic tissues, or in pathological conditions, normal tissues.

Monday will be Adhesion Proteins