The human body is estimated to remove more than 200 billion dead cells every day.
Phagocytes ingest multiple targets in succession and defective clearance of apoptotic cell results in accumulation of apoptotic cell debris, causing severe tissue injuries and has been linked with various inflammatory diseases and autoimmunity.
The role of SLC transporters in efferocytosis
- SLCs mediate the transport of molecules across cell membranes and have key roles in human health. Remarkably, more than 100 Mendelian diseases are caused by a defect in a single solute carrier (SLC) transporter. Genetic studies have provided information on the roles that SLC transporters play in human health and disease. Yet, compared to other gene families of similar stature, SLCs are relatively understudied. We have recently demonstrated that the expression of 33 SLC genes are modulated during efferocytosis. Exciting studies resulting from this project include; the mechanisms of SLC modulation during efferocytosis, regulation of phagocytosis by other SLCs (function), and finally how the SLC-phagocytosis pathway contributes to tissue homeostasis (consequence).
(i) Coordinated regulation of solute carrier (SLC) proteins during cell clearance. We identified a subset of solute carrier (SLC) family genes as coordinately regulated during apoptotic cell engulfment. SLC proteins are important for nutrient uptake, ion transport, and small molecule transport across membranes. Moreover, more than 100 human diseases are linked to SLCs, yet most remain poorly characterized. We established a functional signature database which aggregates known or predicted physiological functions for SLCs and used this to classify phagocytosis-dependent SLCs.
(ii) Apoptotic cell contact drives distinct phagocyte changes, including rapid glucose uptake/glycolytic flux. Based on the SLC network we created from the RNA-seq, we noted a striking requirement for glucose uptake via SLC2A1 during apoptotic cell clearance. Upon engagement with phosphatidylserine (PS) on apoptotic cells this carrier facilitates increased glycolytic flux, fueling actin polymerization. Increased glycolytic flux and corpse digestion leads to solute accumulation that lowers intracellular pH. Accordingly, we found that phagocytes require another SLC (SLC16A1) for lactic acid export, which promotes an anti-inflammatory response.
The effect of enhancing efferocytosis in health and disease
- In addition, utilizing the ‘super-engulfer’ transgenic mice that we developed, we seek to address whether boosting apoptotic cell clearance has beneficial effects on human health. Expression of the hyper active PS receptor showed a dramatic increase in phagocytic ability. Defective clearance of apoptotic cells can result in accumulation of apoptotic cell debris, causing severe tissue injuries and inflammation leading to a variety of diseases such as autoimmune disease. It is therefore vital to find novel ways to ameliorate these diseases.
(iii) Establishment of a novel “Super-engulfer” model systems. In a different set of project, we also have developed a novel way to boost cell corpse clearance by modulating the phosphatidylserine (PtdSer) receptor. The receptor-expressing phagocytes show a striking boost in engulfment, with 5-fold increase in apoptotic cell uptake. We have has also created transgenic mice expressing the hyper active receptor.