Necrotic cell death increases the release of macrophage migration inhibitory factor by monocytes/macrophages

Abstract

Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory molecule with both cytokine and noncytokine activity. MIF is constitutively released from multiple cell types via an unconventional secretory pathway that is not well defined. Here, we looked at MIF release from human and mouse monocytes/macrophages in response to different stimuli. While MIF release was not significantly altered in response to lipopolysaccharide or heat-killed Escherichia coli, cytotoxic stimuli strongly promoted release of MIF. MIF release was highly upregulated in cells undergoing necrosis, necroptosis and NLRP3 inflammasome-dependent pyroptosis. Our data suggest that cell death represents a major route for MIF release from myeloid cells. The functional significance of these findings and their potential importance in the context of autoimmune and inflammatory diseases warrant further investigation.

Revisiting the secretion mechanism(s) of macrophage migration inhibitory factor—welcome to the “UPS club”

“…Studying immortalized mouse bone marrow‐derived macrophages (BMDM) and human THP‐1 monocyte‐like cells, Dankers et al . now offer evidence that MIF release from monocytes/macrophages may be mediated by necrosis, necroptosis and pyroptosis 6 …”

“…and (iii) what are the relative contributions of the different mechanisms in early stage, low-grade inflammatory stimulation versus elevated inflammation versus exuberant hyperstimulation associated with cell damage? The answers will also help to address open questions regarding LPS-triggered MIF secretion from fully viable macrophages such as RAW264.7 or peritoneal exudate macrophages versus BMDMs or human monocytes, 6,22 MIF release mechanisms in other nonimmune cell types or the intriguing observation from single-cell secretion profiles, suggesting the existence of stimulusdependent MIF secretion-competent cells. 23 Regardless of these open mechanistic aspects, our gained knowledge of the MIF secretion mechanism furthers the concept that MIF is a key upstream mediator of monocyte/macrophage inflammation.…”

“…This study by Dankers et al adds an important new facet to its secretion mechanism, linking MIF release to the processes of necroptosis and nucleotide-binding domain, leucine-rich-repeat-containing (NLR) family pyrin domain containing 3 (NLRP3) inflammasome-dependent pyroptosis. 6 The data contribute to establish MIF as a member of the "unconventional protein secretion UPS club of proteins. "…”

“…In fact, the release pattern following necrotic stimulation of macrophages mirrored that of lactate dehydrogenase (LDH) as a representative of an intracellular house-keeping protein. 6 Necroptosis is a programmed form of necrosis, also considered as regulated inflammatory cell death. Unlike in necrosis, permeabilization of the cell membrane during necroptosis is tightly regulated and is mediated by caspase-independent receptorinteracting kinase-1(RIPK1)/RIPK3/ ripoptosome/mixed lineage kinase domain-like pseudokinase (MLKL)mediated pore formation.…”

Necroptosis in Immuno-Oncology and Cancer Immunotherapy

“…Of note, due to lack of systematic comparative studies, it is currently not clear if there exist strong differences between the recruitment patterns of innate immune cells toward necrotic or necroptotic cells. However, published evidence scattered across different studies suggests a largely overlapping monocytes or macrophages-driven chemotactic response to both cell death modalities [61,136,151]. Nevertheless, more comprehensive studies are required to address this gap-in-knowledge.…”