Article Text

PDF
THU0224 Association of IRAK-M with neuropsychiatric symptoms in systemic lupus erythematosus patients
  1. S Sacre,
  2. R Thwaites,
  3. K Davies
  1. Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom

Abstract

Background Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease, where a breakdown in immune tolerance leads to sustained inflammation and tissue damage. Patients exhibit multi-organ involvement with a diverse range of symptoms that include arthritis, nephritis, neuropsychiatric events and dermatological complaints. Interleukin-1 receptor-associated kinase M (IRAK-M), a negative regulator of toll-like receptor (TLR) signalling has previously been associated with SLE in a murine study [1]. Deficiency of IRAK-M was observed to exacerbated disease in a SLE model in C57BL/6-lpr/lpr mice [2].

Objectives This study aimed to investigate the expression of IRAK-M in monocytes from SLE patients compared with healthy control donors and measure downstream cytokine production upon TLR stimulation.

Methods The study was approved by the Brighton East Research Ethics Committee and the National Research Ethics Service Committee North West – Lancaster. Whole venous blood was collected from 39 SLE patients and 19 healthy donors. Peripheral blood mononuclear cells were purified from whole blood after which monocytes were isolated using CD14+ selection beads. Expression of IRAK-M was determined relative to the geometric mean of the housekeeping genes glyceraldehyde 3-phosphate dehydrogenase and hypoxanthine phosphoribosyltransferase 1 by quantitative polymerase chain reaction. Cultured monocytes were stimulated with TLR ligands. Cytokine production was measured by enzyme-linked immunosorbent assay.

Results IRAK-M expression was increased in the SLE patient group, however many of the patients did not show elevated expression compared to healthy donors. When stratified by disease symptoms, a clear correlation was observed between low expression of IRAK-M and neuropsychiatric symptoms which was not evident when evaluating other SLE symptoms. Interestingly, TLR activation led to elevated cytokine production in SLE patient monocytes that correlated with the basal level of IRAK-M expression in individual donors. Further investigation revealed that SLE monocytes demonstrated a reduced upregulation of IRAK-M after TLR activation compared to healthy donors.

Conclusions Increased expression of IRAK-M was not unexpected in the SLE group due to the systemic inflammatory nature of the disease. However, not all patients presented with increased levels of IRAK-M and upon activation were less able to upregulate IRAK-M compared to healthy donors, suggesting a reduced capacity to resolve inflammation. This was reflected in the elevated cytokine production observed from SLE monocytes. Thus, low expression of IRAK-M in SLE monocytes is linked to elevated inflammatory cytokine production and may be a biomarker for neuropsychiatric symptoms in SLE patients.

References

  1. Kobayashi, K., et al. Cell, 2002. 110(2): p. 191–202.

  2. Lech, M., et al. Ann Rheum Dis, 2011. 70(12): p. 2207–17.

References

Acknowledgements Study funded by Brighton and Sussex Medical School.

Disclosure of Interest None declared

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.