RT Journal Article
SR Electronic
T1 344 Linking macrophage migration inhibitory factor and nlrp3 in the pathogenesis of il-1 dependent inflammatory disorders
JF Lupus Science & Medicine
JO Lupus Sci & Med
FD Lupus Foundation of America
SP A151
OP A152
DO 10.1136/lupus-2017-000215.344
VO 4
IS Suppl 1
A1 Lang, T
A1 Lee, J
A1 Pinar, A
A1 Fan, H
A1 Mansell, A
A1 Morand, E
A1 Harris, J
YR 2017
UL http://lupus.bmj.com/content/4/Suppl_1/A151.2.abstract
AB Background and Aims Macrophage migration inhibitory factor (MIF) is a mediator of innate immunity and is implicated in the pathogenesis of numerous autoinflammatory disorders. Clinical studies have shown correlations between elevated levels of IL-1β and MIF in serum with disease outcomes of patients with autoimmune disorders. To date, it is unclear whether MIF specifically regulates the expression and secretion of IL-1 family cytokines. Therefore, we aim to characterise mechanisms by which MIF may modulate the secretion of IL-1 family cytokines.Methods The biological activity of MIF in murine bone marrow derived macrophages (BMDM) was inhibited using a small molecule inhibitor, COR123625. Concurrently, BMDM derived from Mif-/- mice were employed to evaluate the effects of MIF depletion on regulation of IL-1 family cytokines. mRNA expression was analysed by qRTPCR. Protein expression and secretion of IL-1α, IL-1β and IL-18 was assessed by western blot and ELISA.Results We show that depletion of MIF in macrophages significantly reduced IL-1 cytokine release specifically in response to NLRP3 stimuli, but has no effect on the secretion of TNF-α and IL-6. Moreover, diminished IL-1 responses were independent of production of pro-IL-1β. Instead, MIF depletion specifically inhibits NLRP3-mediated IL-1 responses as levels were unaffected following activation of AIM2 or NLRC4 inflammasomes.Conclusions Our findings reveal a novel role for MIF in the modulation of IL-1-dependent inflammatory responses, linking MIF directly to NLRP3 inflammasome activation. This study for the first time implicates a specific role for MIF in the release of IL-1 family cytokines and highlights the potential of targeting MIF in IL-1-dependent pathologies.