The macrophage (MØ)
scavenger receptor (SR-A) belongs to a growing family of molecules
functionally defined by their ability to bind modified forms
of low density lipoprotein (mLDL).
SR-A is a type II, trimeric
transmembrane glycoprotein initially cloned from bovine lung
mRNA.
Three naturally occurring
forms of SR-A have been detected, which are alternative splice
variants of the same gene found on chromosome 8p22. The structure
of each isoform is depicted in the figure below.
SR-A type I (SR-AI) contains
a C-terminal scavenger receptor cysteine-rich domain of 110 amino
acids. A similar protein motif is found on several other molecules
on immune cell surfaces including CD5 and CD6, though its function
is still unclear. Type II and type III SR-A(SR-AII and SR-AIII)
express a short C-terminus or truncated cysteine-rich domain
respectively. SR-AIII is trapped in the endoplasmic reticulum
and has no known ligand-binding activity although it can exert
a dominant negative effect in cells which co-express different
SR-A isoforms.
Besides binding mLDL,
SR-A is able to recognise a broad range of ligands including
polysaccharides and polyribonucleic acids.
All known ligands for
SR-A are polyanionic, although not all negatively charged molecules
are ligands as there are unknown structural criteria for recognition
by the receptor.
The ligand-binding region
is in the positively charged collagenous domain of SR-AI and
SR-AII. No difference in ligand-binding has hitherto been detected
between these isoforms even though they vary in primary structure.
SR-A is expressed by most
tissue MØ, however, its role in vivo is unclear as it
is able to mediate disparate functions in vitro including endocytosis,
phagocytosis and adhesion.
SR-A can endocytose mLDL,
important in foam cell formation and atherosclerosis.
Our laboratory has also
shown SR-A is involved in adhesion in vitro as 2F8, a specific
rat monoclonal antibody, inhibited divalent cation-independent
adhesion of murine MØ-like cells to serum-coated tissue-culture
plastic (TCP).
We demonstrated that MØ
from SR-A knockout (SR-A-/-) mice displayed a reduced capacity
to phagocytose apoptotic thymocytes in vitro.
SR-A is also thought to
have a role in host defence as SR-A-/- mice are more sensitive
to endotoxic shock following BCG challenge, and to Listeria monocytogenes
infection. SR-As broad ligand binding, including recognition
of lipopolysaccharide (LPS), lipoteichoic acid (LTA) and whole
bacteria in vitro, suggest it may protect against bacterial infections.
We have examined the contribution
of SR-A to the internalisation of bacteria by murine MØ
in vitro, which varied with bacterial strain, MØ heterogeneity
and culture conditions.
We would further expect
to find strains of bacteria which use SR-A exclusively and others
enter MØ via SR-A-independent mechanisms.
MØ heterogeneity
also influences the uptake of ligands along with in vitro culture
conditions. Both endocytosis and phagocytosis via SR-A are dramatically
reduced when MØ are plated on serum-coated TCP compared
to bacteriologic plastic, where adhesion is through CR3 rather
than SR-A.
