Just like a large city, the body has a several systems in place to dispose of different types of waste. And when one of these systems malfunctions, serious problems can arise.
Dr. Tracy McGaha, a Senior Scientist at the Princess Margaret Cancer Centre, has shown that disrupting efferocytosis—the process through which dead cells are removed from the body—promotes the development of lupus. The findings of the study were published today in the prestigious journal Nature Immunology.
Lupus occurs when the immune system mistakenly attacks healthy tissues throughout the body, including those of the joints, skin, kidneys, blood, heart and lungs. The abnormal immune response can cause significant inflammation and damage to these parts of the body.
The cause of lupus and the immune mechanisms responsible for its damage remain elusive. This gap in knowledge has precluded the development of effective treatments that target the underlying cause of the disease.
“The link between lupus and efferocytosis is that they both involve the immune system,” explains Dr. McGaha. “In efferocytosis, specialized immune cells known as phagocytes seek out dead cells, then engulf and digest them—acting like the body’s trash collectors.”
The researchers showed that when phagocytes ‘eat’ dead cells, the immune system is suppressed through the action of a protein known as the aryl hydrocarbon receptor (AhR). In contrast, when phagocytes lacking AhR eat dead cells, the immune system is not suppressed and the body attacks healthy tissues, causing damage similar to what seen in lupus.
Dr. McGaha’s team also found that AhR activity can affect disease severity in an experimental model of lupus: disease symptoms worsen when AhR is inhibited, whereas disease symptoms improve when AhR is activated.
Dr. McGaha comments, “the results of our study suggest that AhR activity is a key mechanism that prevents the immune system from attacking normal tissues. We believe that this new knowledge could be exploited to develop new more effective treatments for lupus and to make the immune system better at destroying cells that have become cancerous.”
This work was supported by the National Institutes of Health, the Canada First Research Excellence Fund, the Swedish Medical Research Council, the Karolinska Institute (Sweden), the Canada Foundation for Innovation and The Princess Margaret Cancer Foundation. D De Carvalho holds a Tier 2 Canada Research Chair in Cancer Epigenetics and Epigenetic Therapy.
Shinde R, Hezaveh K, Halaby MJ, Kloetgen A, Charkravarthy A, da Silva Medina T, Deol R, Manion KP, Baglaenko Y, Eldh M, Lamorte S, Wallace D, Chodisetti SB, Ravishankar B, Lui H, Chaudary K, Munn DH, Tsirigos A, Madaio M, Grabrielsson S, Touma Z, Wither J, De Carvalho D, McGaha TL. Apoptotic cell–induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans. Nat Immunol. 2018 June. doi:10.1038/s41590-018-0107-1.