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vertebrates, further underlying the fact that throughout evolution
complement anaphylatoxins and their receptor-mediated pathways
have retained a high degree of structural conservation and functional
homology.
COMPLEMENT MEDIATES NOVEL FUNCTIONS IN DEVELOPMENTAL
PROCESSES
Complement has long been recognized as an arm of innate immunity
that mediates strictly immunological functions, by maintaining host
defense against invading pathogens, and by mediating local and sys-
temic inflammatory responses under various pathophysiological
settings. Recently, however, it has become evident that several comple-
ment components exert novel functions that are associated with
normal biological and developmental processes in various tissues and
cannot be clearly placed in an “inflammatory” context [3,74].
The role of various complement components has been rigorously
investigated in three distinct developmental processes. These include
limb and lens regeneration in urodeles, liver regeneration in mammals,
and stem cell differentiation during hematopoietic development.
Complement Components Promote Hepatocyte Regeneration
The liver is one of the few organs in mammals that have retained
the ability to regenerate, restoring its functional integrity after partial
hepatectomy, or viral or acute toxic injury [75]. The hepatic parenchyma
reacts to these insults by eliciting a robust proliferative response that
causes previously quiescent hepatocytes to reenter the cell cycle and
divide. Several cytokine, hormonal, and growth factor-dependent path-
ways have been implicated in triggering liver regeneration [76-78].
However, to this date, the potential interaction of such hepatocellular
regenerative pathways with components of the innate immune
response has not been addressed. It has been previously shown that
complement is critical for the normal recovery of the liver after acute
toxic challenge [79]. Recently, it was established that complement com-
ponents are essential priming partners in the early growth response of
the liver by showing that complement-mediated pathways are coupled
to the cytokine network that drives the regenerative response of hepa-
tocytes [53]. This study revealed a pivotal role for both anaphylatoxins
C3a and C5a in promoting the growth response of regenerating hepa-
tocytes. Furthermore, it was shown that blockade of C5aR leads to
abrogation of liver regeneration by affecting the normal induction of
cytokines and the early activation of hepatic transcription factors that
are essential for the “priming” of quiescent hepatocytes [53].
Further delineating the mechanisms by which complement proteins
and receptors interact with other signaling networks in the regenerating
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