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.
Phagocytosis of apoptotic cells is fundamentally important for many biological processes, and defects in cell clearance have been linked to multiple inflammatory diseases. Similarly, mutations in solute carrier (Slc) family proteins have been linked to >100 human diseases. This proposal addresses the role of the Slc genes and proteins during the process of apoptotic cell clearance, in the context of inflammation models. Since SLCs are membrane proteins and have been shown to be drug targets, the results of this proposal could have significant therapeutic implications for diseases such as autoimmune diseases, lung inflammation, atherosclerosis, and acute kidney injury, where both the apoptotic cell clearance and SLC function have been previously linked.
