Background/Purpose: The pathologic hallmarks of systemic lupus erythematosus (SLE or lupus) are altered immune responses to nuclear autoantigens with autoantibody production and subsequent tissue injury. Early studies suggested a critical role for adaptive immunity in the development of lupus; however, recent data have expanded this paradigm to a pathogenic role for innate immunity. For instance, TLR7/8 recognize the ssRNA of the self-antigen U1-small nuclear ribonucleorprotein (U1-snRNP) that is targeted by anti-U1-snRNP antibodies (Abs) in lupus.  Indeed, we showed the production of IL-1β from human monocytes (MO) exposed to a combination of U1-snRNP and anti-U1-snRNP Abs by the activation of the caspase-1-containing NLRP3 inflammasome. Macrophage migration inhibitory factor (MIF), primarily produced from MO and macrophages, plays an important role in immune cell function by promoting the production of IL-1, IL-6 and TNF-α, which are increased in blood, skin and/or renal tissues in lupus patients. Recent data have shown an association between serum MIF levels and MIF gene polymorphisms with SLE-related organ damage as well as decreased glomerulonephritis in lupus-prone mice treated with MIF antagonists. However, little is known about the mechanisms underlying MIF production in SLE as well as the functional link between MIF and the NLRP3 inflammasome.  We have addressed these questions using human MO.  

Methods: Human primary MO were purified from peripheral blood mononuclear cells (PBMCs) of healthy donors and incubated in the presence or absence of U1-snRNP and/or anti-U1-snRNP Ab+ or healthy serum with or without the MIF inhibitor MIF098.  Tissue culture supernatants and cells were analyzed for MIF, IL-1β, NLRP3 and NF-kB by ELISA, flow cytometry and Western blotting.

Results: A combination of U1-snRNP and anti-U1-snRNP Ab+ serum (hereafter snRNP immune complex or IC) induced the production of MIF and IL-1β from freshly purified human MO. However, U1-sNRNP, anti-U1-snRNP alone, or a combination of U1-snRNP and healthy serum did not induce the production of these cytokines from the same cells. The small molecule MIF inhibitor MIF098, which interferes with the binding of MIF to its receptor, decreased the production of IL-1β from MO in response to the snRNP IC, suggesting a co-stimulatory role for MIF in the activation of the NLRP3 inflammasome. Indeed, the MIF inhibitor MIF098 substantially reduced the expression of NLRP3, a critical component of the NLRP3 inflammasome, in MO in response to the snRNP IC. This phenomenon is likely mediated in part by the suppression of NF-kB activation, which can up-regulate the expression of NLRP3, since MIF098 also suppressed the activation of NF-kB. Moreover, adding exogenous MIF during the incubation of MO with snRNP IC increased IL-1β production.

Conclusion: These results are the first to demonstrate the inducible production of MIF from MO by lupus snRNP IC and support MIF action in regulating the NLRP3 inflammasome in human MO. These data also provide a functional link for an association of high expression MIF alleles with SLE and a rationale for targeting MIF in human disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-sle-susceptibility-gene-macrophage-migration-inhibitory-factor-serves-as-an-upstream-regulator-of-nlrp3-nod-like-receptor-family-pyrin-domain-containing-3-expression-and-subsequent-il-1beta/