Homotrimeric Macrophage Migration Inhibitory Factor (MIF) Drives Inflammatory Responses in the Corneal Epithelium by Promoting Caveolin-rich Platform Assembly in Response to Infection

Reidy, Thomas; Rittenberg, Alexander; Dwyer, Markryan; D'Ortona, Samantha; Pier, Gerald B.; Gadjeva, Mihaela

doi:10.1074/jbc.m112.351064

Cited by 12 publications

(13 citation statements)

References 47 publications

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“…Recent screening for intracellular pathways that stimulated NET release showed that activation of the MAPK p44/p45 pathway promoted NETosis over apoptosis [29]. Since we and others have reported that the endogenous cytokine MIF is rapidly released in response to infectious challenge and stimulates MAPK activation [17,30], the influence of MIF on NETosis was evaluated [31]. When MIF-deficient PMNs that were purified from MIF knock-out mice and were exposed to P. aeruginosa PAO1 , the resulting MAPK activation was sustained upon reconstitution with 100 ng rMIF as evident by the elevated phosphorylation state of p42//p44 at 30 min and 60 min post infection (Figure 5).…”

Section: Resultsmentioning

confidence: 99%

“…rMIF protein was produced in E. coli BL21 Star (DE3) cells (Invitrogen), after induction with 1mM IPTG for 3.5 hours as in [17]. Bacterial cells were pelleted by centrifugation in a Beckman Allegra 6R centrifuge (3,000 rpm, 15 min, ambient temperature).…”

Section: Methodsmentioning

confidence: 99%

“…MIF is a “danger” signal, released in response to pathogenic stimuli with potent pro-inflammatory functions. Extracellular MIF is recognized by an array of receptors, including CD74 [12], CXCR2 [13], CXCR4 [14] and CXCR7 [15], to promote cellular survival and maintain proinflammatory cytokine synthesis [16,17]. MIF overrides the anti-inflammatory activities of corticosteroids [18] which makes it an attractive molecule to investigate in the context of neutrophil-rich corticosteroid-resistant inflammation in CF.…”

Section: Introductionmentioning

confidence: 99%

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Cystic Fibrosis Sputum DNA Has NETosis Characteristics and Neutrophil Extracellular Trap Release Is Regulated by Macrophage Migration-Inhibitory Factor

Dwyer

Shan²,

D'Ortona³

et al. 2014

J Innate Immun

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178

165

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Neutrophils are the main proinflammatory cell type in chronically infected lungs of cystic fibrosis (CF) patients; however, they fail to effectively clear the colonizing pathogens. Here, we investigated the molecular composition of non-mucoid and mucoid Pseudomonas aeruginosa-induced neutrophil extracellular traps (NETs) in vitro and compared them to the DNA-protein complexes present in the CF sputum. The protein composition of P. aeruginosa-induced NET fragments revealed that irrespective of the inducing stimuli, NET fragments were decorated with a conserved set of proteins. The DNA-protein complexes derived from CF sputum were consistent with NETosis and shared a similar protein signature, suggesting that the majority of the extracellular DNA was NET derived. The ability of polymorphonuclear leukocytes to produce NETs in response to P. aeruginosa was driven by macrophage migration-inhibitory factor (MIF) by promoting mitogen-activated protein kinase. Analysis of 132 CF patient samples revealed that elevated MIF protein levels correlated with poorer lung function. We suggest that targeting MIF by small molecular inhibitors might reduce the presence of extracellular DNA and serve as an adjunct to the use of antimicrobial drugs that could ultimately reduce bacterial fitness in the lungs during the later stages of CF disease.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cystic Fibrosis Sputum DNA Has NETosis Characteristics and Neutrophil Extracellular Trap Release Is Regulated by Macrophage Migration-Inhibitory Factor

Dwyer

Shan²,

D'Ortona³

et al. 2014

J Innate Immun

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178

165

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“…Collectively, these results demonstrate that both pathological adenovirus infection and adenoviral gene transfer utilize caveolae to infect the corneal epithelium. In addition to viral pathogens, infection of the corneal epithelium with Pseudomonas aeruginosa drives inflammatory signaling via macrophage migration inhibitory factor (MIF) by assembling caveolin-1-rich signaling platforms (Reidy et al, 2013). The Pseudomonas aeruginosa and MIF-dependent activation of the pro-inflammatory cytokine, interleukin-8, was suppressed by silencing of Cav-1.…”

Section: Caveolins/caveolae In Other Ocular Cellsmentioning

confidence: 99%

Caveolins and caveolae in ocular physiology and pathophysiology

Reagan

McClellan

et al. 2017

Progress in Retinal and Eye Research

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Caveolae are specialized, invaginated plasma membrane domains that are defined morphologically and by the expression of signature proteins called, caveolins. Caveolae and caveolins are abundant in a variety of cell types including vascular endothelium, glia, and fibroblasts where they play critical roles in transcellular transport, endocytosis, mechanotransduction, cell proliferation, membrane lipid homeostasis, and signal transduction. Given these critical cellular functions, it is surprising that ablation of the caveolae organelle does not result in lethality suggesting instead that caveolae and caveolins play modulatory roles in cellular homeostasis. Caveolar components are also expressed in ocular cell types including retinal vascular cells, Müller glia, retinal pigment epithelium (RPE), conventional aqueous humor outflow cells, the corneal epithelium and endothelium, and the lens epithelium. In the eye, studies of caveolae and other membrane microdomains (i.e., “lipid rafts”) have lagged behind what is a substantial body of literature outside vision science. However, interest in caveolae and their molecular components has increased with accumulating evidence of important roles in vision-related functions such as blood-retinal barrier homeostasis, ocular inflammatory signalling, pathogen entry at the ocular surface, and aqueous humor drainage. The recent association of CAV1/2 gene loci with primary open angle glaucoma and intraocular pressure has further enhanced the need to better understand caveolar functions in the context of ocular physiology and disease. Herein, we provide the first comprehensive review of literature on caveolae, caveolins, and other membrane domains in the context of visual system function. This review highlights the importance of caveolae domains and their components in ocular physiology and pathophysiology and emphasizes the need to better understand these important modulators of cellular function.

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“…Although the crystal structure of MIF indicates that it is a trimer, other methods have been used to identify MIF monomers or dimers, in addition to the trimer (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Sedimentation velocity and equilibrium ultracentrifugation data found MIF to be 97-98% trimeric species with a small amount of a large aggregate and an "incompetent monomer" not in equilibrium with the trimer (23).…”

mentioning

confidence: 99%

MIF intersubunit disulfide mutant antagonist supports activation of CD74 by endogenous MIF trimer at physiologic concentrations

Fan

Rajasekaran²,

Syed

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine. In addition to its known receptor-mediated biological activities, MIF possesses a catalytic site of unknown function between subunits of a homotrimer. Each subunit contributes three β-strands to adjacent subunits to form a core seven-stranded β-sheet for each monomer. MIF monomers, dimers, or trimers have been reported, but the active form that binds and activates the MIF receptor (CD74) is still a matter of debate. A cysteine mutant (N110C) that covalently locks MIF into a trimer by forming a disulfide with Cys-80 of an adjacent subunit is used to study this issue. Partial catalytic activity and receptor binding to CD74 are retained by N110C (locked trimer), but there is no cellular signaling. Wild-type MIF-induced cellular signaling, in vivo lung neutrophil accumulation, and alveolar permeability are inhibited with a fivefold excess of N110C. NMR and size-exclusion chromatography with light scattering reveal that N110C can form a higher-order oligomer in equilibrium with a single locked trimer. The X-ray structure confirms a local conformational change that disrupts the subunit interface and results in global changes responsible for the oligomeric form. The structure also confirms these changes are consistent for the partial catalytic and receptor binding activities. The absence of any potential monomer and the retention of partial catalytic and receptor binding activities despite changes in conformation (and dynamics) in the mutant support an endogenous MIF trimer that binds and activates CD74 at nanomolar concentrations. This conclusion has implications for therapeutic development.mechanism | thermostable variant | ERK-1/2 activation M acrophage migration inhibitory factor (MIF) is a proinflammatory protein and an important regulator of innate and adaptive immunity (1). It localizes to the cytosol of all human nucleated cells and is released upon cellular stress to activate the receptor CD74 in complex with its signaling component CD44, or the chemokine receptors CXCR2 and CXCR4 to induce extracellular signal-regulated kinase 1/2 (ERK-1/2) activation (1-3). MIF promotes the cellular secretion of CXCL8, prostaglandin E2 (PGE 2 ), and other proinflammatory mediators, and it inhibits the anti-inflammatory activities of glucocorticoids (4). In addition to inflammation, MIF plays important roles in other diseases and is a drug target in phase I clinical trials for solid tumors (5, 6). MIF is a trimer with extensive subunit-subunit interactions, including a seven-stranded β-sheet for each monomer with β-strands contributed by adjacent subunits (7-9). An enzymatic site with an unknown substrate and a presumed tautomerase/isomerase activity exists between subunits similar to other proteins in the MIF superfamily (10). A key feature of these proteins is an invariant N-terminal residue, Pro-1, that functions as a catalytic base (11).Oligomerization plays an important role in the activity and regulation of a wide variety of proteins (12). Altho...

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Homotrimeric Macrophage Migration Inhibitory Factor (MIF) Drives Inflammatory Responses in the Corneal Epithelium by Promoting Caveolin-rich Platform Assembly in Response to Infection

Cited by 12 publications

References 47 publications

Cystic Fibrosis Sputum DNA Has NETosis Characteristics and Neutrophil Extracellular Trap Release Is Regulated by Macrophage Migration-Inhibitory Factor

Cystic Fibrosis Sputum DNA Has NETosis Characteristics and Neutrophil Extracellular Trap Release Is Regulated by Macrophage Migration-Inhibitory Factor

Caveolins and caveolae in ocular physiology and pathophysiology

MIF intersubunit disulfide mutant antagonist supports activation of CD74 by endogenous MIF trimer at physiologic concentrations

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