Monocytes and Macrophages

1
Monocytes and Macrophages
Michael Fishbein. Role of macrophages in
diagnostic interpretation of endomyocardial
biopsies. Tim Johnson. Is transglutaminase the
switch between inflammation and scarring in
chronic allogaft nephropathy. David Kluth.
Transfected macrophages in renal
inflammation. Alex Magil. Monocyte/macrophages
in renal inflammation. Jeremy Hughes. Resolution
of injury, apoptosis and macrophages.
2
Macrophage Localisation
From Gordon 2002
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Differential Macrophage Activation
Histotoxic NO generation ADCC etc
IFN-?
Reparative IGF-1 Apoptotic cells
TNF
TGF?
Inflammatory Enzymes
4
Macrophages in Inflammation
Classical activation
Programmed NO generation
Innate activation
Non-programmed NO generation
5
How do macrophages integrate conflicting signals
?
TNF
INF?
IL-13
TGF?
LPS
MCP-1
IL-10
IgG
IL-12
RANTES
C3b
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Macrophage Programming
IFN?
NO generation
TNF?
Apoptotic cell uptake
Macrophages activated by certain cytokines are
refractory to other activating cytokines
7
Monocytes and Macrophages
Michael Fishbein. Role of macrophages in
diagnostic interpretation of endomyocardial
biopsies. Alex Magil. Monocyte/macrophages in
renal inflammation. Jeremy Hughes. Resolution of
injury, apoptosis and macrophages. David Kluth.
Transfected macrophages in renal
inflammation. Tim Johnson. Is transglutaminase
the switch between inflammation and scarring in
chronic allogaft nephropathy.
8

• Michael Fishbein. Role of macrophages in
  diagnostic interpretation of endomyocardial
  biopsies.
• Distinguishing between acute rejection and Quilty
  lesions in cardiac allograft biopsies.
• Quilty lesions contain B cells and T cells but
  very few
• macrophages.
• Many macrophages in acute rejection.
• Alex Magil. Monocyte/macrophages in renal
  inflammation.
• Use of macrophage infiltration in diagnosis of
  humoral rejection.
• Glomerular and tubulo-interstitial macrophages
  associated with
• C4d deposition.
• Presence of macrophages associated with poor
  outcomes

9
Jeremy Hughes. Resolution of injury, apoptosis
and macrophages.

• Discussed the role of macrophages in disposal of
  dead
• and dying cells.
• Macrophages the key cell in disposal of both
  necrotic and
• apoptotic cells
• Described the multiple receptors responsible for
  uptake of
• apoptotic cells, including the phosphydyl
  seriene receptor.
• Uptake of apoptotic cells induces an
  anti-inflammatory
• phenotype in macrophages (and so does ligation
  of PSR)
• Overwhelming the normal mechanisms of disposal
  results
• in inflammation.

10
David Kluth. Transfected macrophages in renal
inflammation.

• Discussed the various functional types of
  macrophages and showed that anti-inflammatory
  macrophages can have profound effects in vivo.
• Described the well recognised phenotypes -
  activated, innate activated,
• alternatively activated, type 2 regulatory, and
  anti-inflammatory.
• Showed that thransfected macrophages expressing
  either IL-4 or IL-10 but
• not TGF? reduce acute experimental glomerular
  injury.
• These macrophages localise only to the kidney in
  which they are injected
• but inflammation reduced in both kidneys.
• Introduction of macrophages with blocked NF?B
  are also anti-
• inflammatory, but only in the kidney into which
  the cells were injected

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Localisation of cytokine expressing macrophages
Recombinant Adenoviruses Ad-IL-10
Ad-IL-4 Ad-TGF?
1?106 PKH26 labelled transfected macrophages
injected into left renal artery
12
David Kluth. Transfected macrophages in renal
inflammation.

• Discussed the various functional types of
  macrophages and showed that anti-inflammatory
  macrophages can have profound effects in vivo.
• Described the well recognised phenotypes -
  activated, innate activated,
• alternatively activated, type 2 regulatory, and
  anti-inflammatory.
• Showed that thransfected macrophages expressing
  either IL-4 or IL-10 but
• not TGF? reduce acute experimental glomerular
  injury.
• These macrophages localise only to the kidney in
  which they are injected
• but inflammation reduced in both kidneys.
• Introduction of macrophages with blocked NF?B
  are also anti-
• inflammatory, but only in the kidney into which
  the cells were injected

13
Tim Johnson. Is transglutaminase the switch
between inflammation and scarring in chronic
allogaft nephropathy.

• Discussed the role of tissue transglutaminases in
  cell death and in matrix accumulation.
• Demonstrated all models of chronic renal scarring
  are associated
• with increased expression of tissue
  transglutaminases.
• Expression associated with increased cross
  linking of collagen
• and with increased TGF? expression.
• Tubular cells were the source of tTGs in models
  of scarring in
• native kidneys but interstitial (macrophages)
  in chronic scarring
• in allografts.

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Conclusions
Macrophages are numerous in all forms renal
injury. Macrophages have numerous different
functions that may be injurious or
reparative. Key issues for the future to devise
a more complete understanding of the range of
macrophage activities, how to identify macrophage
phenotypes in vivo and how to manipulate
macrophage function as therapy.