Publications

Macrophage migration inhibitory factor regulates U1-snRNP immune complex mediated activation of the NLRP3 inflammasome

Shin, M.S., Kang, Y., Wahl, E.R. et al.

OBJECTIVE:
High expression alleles of macrophage migration inhibitory factor (MIF) are linked genetically to SLE disease severity. The U1-snRNP (snRNP) immune complex containing U1-snRNP and anti-U1-snRNP antibodies, which are found in SLE, activates the NLRP3 inflammasome comprised of NLRP3, ASC, and procaspase-1 in human monocytes, leading to the production of IL-1β. The role of the snRNP immune complex in upregulating the MIF and its interface with the NLRP3 inflammasome were investigated.

METHODS:
MIF, IL-1β, NLRP3, caspase-1, ASC, and MIF receptors were analyzed in human monocytes incubated with or without the snRNP immune complex by ELISA, Western blot, qPCR, and CyTOF. MIF pathway responses were probed with the novel small molecule antagonist MIF098.

RESULTS:
The snRNP immune complex induced the production of MIF and IL-1β from human monocytes. High-dimensional single cell CyTOF analysis established MIF regulation of inflammasome activation, including a quantitative relationship in MIF, its receptors, and IL-1β, in monocytes. MIF098, which blocks MIF binding to its cognate receptor, suppressed IL-1β production and NLRP3 upregulation, a rate-limiting step in activating the NLRP3 inflammasome, as well as caspase-1 activation in snRNP immune complex-stimulated human monocytes.

CONCLUSION:
The U1-snRNP immune complex is a specific stimulus of MIF production in human monocytes, with MIF having an upstream role in defining the inflammatory characteristics of activated monocytes by regulating NLRP3 inflammasome activation and downstream IL-1β production. These findings provide mechanistic insight and a therapeutic rationale for targeting MIF in subgroups of lupus patients, such as high genotypic MIF expressers or those with anti-snRNP antibodies.

Citation

Shin, M.S., Kang, Y., Wahl, E.R. et al. "Macrophage migration inhibitory factor regulates U1-snRNP immune complex mediated activation of the NLRP3 inflammasome" Arthritis and Rheumatology (2018): 109–20