Migration inhibitory factor (MIF) is released following lytic cell death: Possible role as a DAMP — ASN Events
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  3. Migration inhibitory factor (MIF) is released following lytic cell death: Possible role as a DAMP

Migration inhibitory factor (MIF) is released following lytic cell death: Possible role as a DAMP (#415)

shahrzad zamani 1 , Tali Lang 1 , Jacinta P.W. thomas 1 , Eric Morand 1 , James Harris 1
  1. Rheumatic Diseases Research Group, Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia

INTRODUCTION: Damage-associated molecular pattern (DAMP) molecules are passively released by cells undergoing lytic death and are associated with tissue damage in several inflammatory and autoimmune conditions. Macrophage migration inhibitory factor (MIF), expressed by monocyte/macrophages, can act as a pro-inflammatory cytokine and has a pathogenic role in some inflammatory diseases, including rheumatoid arthritis and systemic lupus erythematosus. How MIF is secreted/released is not well understood, although one study has demonstrated that neutrophils release it following necrotic cell death [1]. Here, we looked at the release of MIF in response to different forms of cell death in monocyte/macrophages.

METHODS: Human THP-1 monocytes were treated with inducers of necrosis (ethanol, 1.25-25%), apoptosis (staurosporine, 10-5-10-9 M), pyroptosis (LPS, 100 ng/ml + nigericin, 10 µM) and necroptosis (BV-6, 1 µM + rhTNF-α, 30ng/ml + Z-VAD-FMK, 50 µM). Cell death was measured using a combination of Annexin V/PI staining and SYTOX® Green stain and MIF release was measured by ELISA. In some experiments, caspase inhibitors were also included to abrogate cell death.

RESULTS: MIF release correlated with necrosis/cell lysis, but not with early apoptosis. Moreover, in most cases, LPS had no additional effect on MIF release. We also demonstrate for the first time that MIF is released in response to both NLRP3-dependent pyroptosis and RIPK1-depedent necroptosis.

CONCLUSIONS: Our data suggest that MIF release correlates with necrotic but not apoptotic modes of cell death in monocytes, suggesting that it is released passively following cell lysis. Interestingly. MIF release was not dependent on LPS treatment which may have significant implications for sterile inflammation. However, it remains to be determined whether this released MIF is bioactive and functions as a DAMP.  

1- Roth, S., et al., Secondary necrotic neutrophils release interleukin-16C and macrophage migration inhibitory factor from stores in the cytosol. Cell death discovery, 2015. 1: p. 15056.

  

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