Abstract: SOLUTE CARRIER (SLC) PROTEINS IN EFFEROCYTOSIS AND INFLAMMATION:
It is truly remarkable that our bodies turn over on average about one million cells every second of life. The cells that
are turned over, predominantly by the process of apoptosis, include excess cells generated as part of normal
development, used/aged cells, and damaged cells arising from disease or infections. The efficient removal of such
apoptotic cells is important for ‘making space’ for replacement by living cells, preventing inflammation, maintaining
the function of the tissue/organ, and in turn, a healthy organism. The efficient removal of the dying cells occurs via the
process of ‘efferocytosis’, and is done by professional phagocytes (such as macrophages and immature dendritic
cells) or neighboring cells (e.g. fibroblasts, epithelial cells) within a given tissue. Efferocytosis, which involves ligands
on apoptotic cells and specific receptors on phagocytes, is very efficient, and actively anti-inflammatory. However,
impaired clearance of apoptotic cells results in the accumulation of dead cells, and the resulting chronic inflammation
linked to a number of pathological conditions such as atherosclerosis, lung inflammation, and inflammatory bowel
diseases. While significant progress has been made in understanding apoptotic cell recognition and efferocytic uptake
in recent years, significant gaps remain.
Solute carrier (SLC) proteins are membrane proteins that selectively conduct ions, metabolites, and aminoacids
across the plasma membrane, and specific internal cellular membranes. In the human genome, SLCs represent the
second largest family (after the GPCRs), with ~400 SLC family members. Despite ~100 human diseases being linked
to mutations in SLC genes, the SLC family is relatively understided, including in the immune system 7,8. This may in
part be because the SLCs functionally characterized have often been in isolation, and not many SLCs are studied as
part of a larger biological process. Recently, while studying phagocytes taking up apoptotic cells, we unexpectedly
came across a coordinated regulation of >30 members of the Slc gene family (Morioka et al., Nature 2018; Perry et al,
Nature Cell Biol., 2019). This proposal tests the hypothesis that SLC proteins can play key roles in different phases of
efferocytosis, and that sequential use of specific SLCs during efferocytosis facilitates communication between
phagocytes contributes to maintaining an anti-inflammatory state within tissues.