“Failure to Appropriately Digest” as a new model of lupus pathogenesis

Apoptosis is a natural process where cells die and are cleared away, which is essential for many bodily functions, including development and immune cell maintenance. The process of removing dead cells, known as efferocytosis, is crucial for preventing harmful inflammation. Tissue-resident macrophages (TRMs) are specialized cells that perform efferocytosis by engulfing and digesting these dead cells. However, if this process is faulty, it may lead to diseases like systemic lupus erythematosus (SLE). Traditional models suggest that SLE occurs due to a failure in clearing dead cells, but recent findings by Dr. Perry suggest that the problem might actually lie in how these cells are digested once they are engulfed.

Dr. Perry will explore how macrophages manage the potentially dangerous biological material from dead cells. He will investigate how specific proteins called SLLC12A2 and WNK1 affect macrophages’ ability to digest dead cells. He will examine whether eliminating SLC12A2 in macrophages results in lupus-like features in mice. Certain systems within macrophages help them handle the continuous influx of material from dead cells. These systems, called rapid response circuits, quickly sense and respond to changes caused by the dead cells’ contents. Dr. Perry will study specific proteins that are critical for this process, particularly those that are linked to genetic variants associated with SLE.

What this means for people with lupus

Findings from Dr. Perry’s study could lead to new insights into the mechanisms behind SLE, potentially shifting the focus from enhancing cell clearance to improving how dead cells are digested. This could result in new treatments that help macrophages manage dead cells more safely, reducing inflammation and improving the lives of people with lupus.

The human body is estimated to remove 1% of its body mass, likely more than 200 billion cells, every day. To achieve this, we rely on apoptotic cell (AC) clearance, also known as ‘efferocytosis’. Efferocytosis is carried out by tissue-resident macrophages (TRMs) that are numerically fewer than the number of neighboring cells that die. Because TRMs often ingest multiple ACs in quick succession, accumulation of AC cargo poses a significant risk to homeostasis of the cell and ultimately the host. Current models suggest that Systemic Lupus Erythematosus (SLE) occurs because of AC clearance. However, the majority of SLE patients do not present with overt AC clearance defects. We reasoned that to understand the role of efferocytosis in SLE, we must first expand our understanding of efferocytosis itself. We recently found that chloride sensing/flux via a SLC12/WNK1 pathway acts to ‘accelerate’ or ‘brake’ AC engulfment in response to AC internalization. Strikingly, SLC12/WNK1 pathway perturbations that increased AC uptake also induced robust hyper-inflammation. Given this, we propose rethinking the prevailing ‘failure to appropriately clear’ model, which suggests that AC uptake alone is sufficient to maintain homeostasis. SLE arises because of inflammatory mediators released from uncleared ACs that become necrotic. In contrast, our findings suggest that efferocytosis is inherently dangerous, requiring active mechanisms to detect AC content and rapidly initiate compensatory responses to maintain homeostasis. In this model, SLE arises because of a failure to appropriately digest (FAD) ACs.

If FAD is correct, then TRMs must use systems to rapidly assess and respond to changes induced by ingested AC content. Our previous findings lead us to propose that kinases (such as WNK1) function as part of rapid response circuits (RRCs), activating in response to solute change and regulating solute transporters (SLCs) function to impart corrective solute flux. We hypothesize that RRCs are essential for TRMs to manage AC digestion and that abnormal AC digestion underlies SLE development. Here, we will combine expertise in immunology, cell biology, and computational biology to investigate the following:

1) We will assess the consequences of macrophage-specific WNK1 and SLC12A2 disruption in vivo, investigate the mechanism linking the SLC12 pathway to the observed hyper-inflammatory phenotype, and test if SLC12A2 is required for ‘healthy’ efferocytosis human pluripotent stem cell-derived macrophages bearing SNPs identified in patients who suffer from a SLE-like disease.

2) Using novel methods developed in our lab, we recently mapped the transcriptional landscapes of macrophages during and after AC degradation, identifying several candidates, including SLE genetic variants, putatively required for appropriate apoptotic cell digestion. Then, we will begin to mechanistically study putative efferocytosis RRCs and determine how these go awry in SLE.