This week we profile a recent publication in Immunity from the laboratory of Dr. Wilfred
Jefferies at the Michael Smith Labs and the Vancouver Prostate Centre at UBC.
What is the significance of the findings in this publication?
We conducted a gene expression screen to identify genes controlling innate and adaptive immunity, and ABCF1, an ATP-Binding Cassette gene, was identified as a potential regulator of immunity and inflammation. Our interest was further sparked because others had shown that ABCF1 expression is elevated in the synovial fluid of rheumatoid arthritis patients and the ABCF1 gene had also been mapped as a susceptibility risk gene for autoimmune pancreatitis.
At the heart of our study is the use of a genetic approach to establish the function of a gene and to model immune dysfunction in disease. We examined the role of ABCF1 during inflammation and resolution of inflammation in sepsis. Sepsis is a bi-phasic disease, meaning it occurs in two phases: the initial hyper-inflammatory phase called systemic inflammatory response syndrome (SIRS), also referred to as ‘Cytokine Storm’, and the immune-compromised phase called endotoxin tolerance (ET). The SIRS phase leads to a drastic increase in pro-inflammatory immune responses.
As part of our study we discovered that ABCF1 has a new enzymatic function which has never been identified in this class of protein. The ATP-binding cassette (ABC) family protein, ABCF1, has E2 ubiquitin-conjugating activity and regulates this shift, by modulating Toll-like receptor 4 (TLR4) signalling and macrophage polarization.
Immediately following exposure to lipopolysaccharide (LPS) endotoxin, TLR4 signalling from the cell surface of macrophages leads to MyD88-dependent signalling and the induction of pro-inflammatory cytokines. TLR4 is then internalized into endosomes from where it mediates TIR domain-containing adaptor inducing IFNβ (TRIF)-dependent signalling and subsequent production of type I interferons and anti-inflammatory cytokines to promote endotoxin tolerance.
It acts as a molecular switch in sepsis to transition from the initial SIRS phase into the ET phase, thus regulating the chemical balance during sepsis to enhance survival. The ABCF1 switch facilitated anti-inflammatory responses that occur in the ET phase; however, without the ABCF1 switch, responses are stalled in the pro-inflammatory SIRS phase, causing severe tissue damage and death. For example, during SIRS, the presence of endotoxin in the blood (endotoxemia) leads to the upregulation of TNFa, which alters renal microcirculation and hemodynamics, and leads to acute kidney injury (Ramseyer and Garvin, 2013, Doi, 2016). This alteration during sepsis results in hypoperfusion of the kidneys (Vincent et al., 2006). The acute inflammatory response caused by pro-inflammatory cytokines damages the host tissue, which ultimately leads to death (Harty, 2014).
Histological analysis of the ABCF1 deficient mice in the SIRS phase revealed widespread dilation and congestion of small vessels in their kidneys. In addition, histological analysis in the kidneys of the ABCF1 deficient mice in the SIRS phase clearly demonstrated the ‘sludging’ effect of red blood cells being compacted together in dilated/congested vessels. This form of vasculature dilation and congestion on a systemic scale exacerbated in the ABCF1 deficient mice in the SIRS phase results in a critical drop in blood pressure, causing insufficient blood and oxygen to reach critical central organs, including the brain and heart.
What are the next steps for this research?
Since ABCF1 switches off pro-inflammatory pathways, this research may map a path towards new treatments for chronic and acute inflammatory diseases, as well as autoimmune disorders. Specifically, we are currently seeking additional funding to create targeted therapies that halt inflammatory diseases and autoimmune disorders such as rheumatoid arthritis, inflammatory bowel disease, Crohn’s disease, and ulcerative colitis.
This work was funded by:
The research was supported by the Canadian Federal Government’s Canadian Institute for Health Research.
