Impaired recognition and clearance of cellular debris are important factors in the pathogenesis of systemic lupus erythematosus (SLE). A new study sheds light on the mechanisms that regulate immune tolerance to cell debris, suggesting a key role for the transcription factor AhR. “Cell death can have a profound impact on immunity,” states Tracy McGaha. “When cells become apoptotic they can drive immune-suppressive mechanisms that prevent immune reactivity against dying cell-associated antigens. This process is believed to be a key mechanism in the prevention of autoimmunity.”
By studying changes in gene expression in murine phagocytes co-cultured with apoptotic cells, the researchers identified upregulation of AhR-responsive genes following exposure to cell debris. AhR specifically interacted with promoters to upregulate genes encoding cytokines such as IL-10; these changes induced a shift in phagocytes exposed to apoptotic cell debris towards an immunoregulatory phenotype. Blocking AhR led to reduced IL-10 production and a shift towards the production of pro-inflammatory cytokines, suggesting that AhR functions as a regulator of immune tolerance by suppressing inflammatory responses to cellular debris.
Using bone marrow-derived macrophages from Toll-like receptor 9 (Tlr9)-deficient mice, McGaha and colleagues revealed that the recognition of DNA from apoptotic cells by TLR9 can cause AhR activation and the production of IL-10. In two different mouse models of spontaneous lupus-like disease, pharmacological manipulation of AhR activity altered disease severity and progression. Blocking AhR activity increased the severity of lupus-like disease, whereas an AhR agonist ameliorated lupus-like disease. Interestingly, apoptotic cells also activated AhR and induced IL-10 production in human myeloid cells, and AhR transcriptional signatures similar to those seen in lupus-prone mice were seen in myeloid cells from patients with SLE. “Targeting AhR in human disease may have a similar therapeutic effect on disease activity to that seen in mice,” concludes McGaha.
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Shinde, R. et al. Apoptotic cell–induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans. Nat. Immunol. https://doi.org/10.1038/s41590-018-0107-1 (2018)
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This article is modified from the original in Nat. Rev. Rheumatol. (https://doi.org/10.1038/s41584-018-0024-6).
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Collison, J. AhR in SLE. Nat Rev Nephrol 14, 476 (2018). https://doi.org/10.1038/s41581-018-0027-1
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DOI: https://doi.org/10.1038/s41581-018-0027-1