Homotrimeric macrophage migration inhibitory factor (MIF) drives inflammatory responses in the corneal epithelium by promoting caveolin-rich platform assembly in response to infection.

Acute inflammation that arises during Pseudomonas aeruginosa-induced ocular infection can trigger tissue damage resulting in long term impairment of visual function, suggesting that the appropriate treatment strategy should include the use of anti-inflammatory agents in addition to antibiotics. We recently identified a potential target for modulation during ocular infection, macrophage migration inhibitory factor (MIF). MIF deficiency protected mice from inflammatory-mediated corneal damage resulting from acute bacterial keratitis. To gain a better understanding of the molecular mechanisms of MIF activity, we analyzed the oligomeric states and functional properties of MIF during infection. We found that in human primary corneal cells infected with P. aeruginosa, MIF is primarily in a homotrimeric state. Homotrimeric MIF levels correlated with the severity of infection in the corneas of infected mice, suggesting that the MIF homotrimers were the functionally active form of MIF. During infection, human primary corneal cells released more IL-8 when treated with recombinant, locked MIF trimers than when treated with lower MIF oligomers. MIF promoted P. aeruginosa-induced IL-8 responses via the formation of caveolin-1-rich "signaling hubs" in the corneal cells that led to elevated MAPK p42/p44 activation and sustained inflammatory signaling. These findings suggest that inhibiting homotrimerization of MIF or the functional activities of MIF homotrimers could have therapeutic benefits during ocular inflammation.

Correlates of alcohol use disorder pharmacotherapy receipt in medically insured patients.

BACKGROUND: Alcohol use disorder is a highly prevalent disease with multiple medications available for treatment. The overall prevalence of patients receiving pharmacotherapy is believed to be low and the characteristics and comorbidities that affect receipt are not well-established. METHODS: We created a dataset from Truven Health Analytics MarketScan Commercial Claims and Encounters Database of patients with an outpatient encounter for alcohol abuse or dependence in 2014. We subsequently identified patient characteristics, comorbid medical, psychiatric, or substance use disorders, as well as encounter provider specialties and, using multivariable logistic regression, assessed which variables correlated with increased or decreased receipt of pharmacotherapy for alcohol use disorder for this population. RESULTS: In our dataset of 123,355 patients, patient receipt of pharmacotherapy for alcohol use disorder was 3.3 %, and 9.3 % when restricted to the former diagnosis of alcohol dependence only. Male sex, younger age, alcohol-related liver disease, and cannabis use disorders correlated with decreased receipt whereas comorbid major depressive disorders and anxiety disorders correlated with increased receipt. Compared to patients seen by psychiatrists, those seen by primary medical doctors had a lower odds of receiving pharmacotherapy. CONCLUSIONS: Pharmacotherapy for alcohol use disorder is an underutilized treatment modality with a low prevalence of prescription in insured individuals. Patients with specific characteristics and comorbidities are less likely to receive this treatment and greater focus on these patients and in the primary care setting can allow for increased prescribing of these medications.

Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts.

Although most nephron segments contain one type of epithelial cell, the collecting ducts consists of at least two: intercalated (IC) and principal (PC) cells, which regulate acid-base and salt-water homeostasis, respectively. In adult kidneys, these cells are organized in rosettes suggesting functional interactions. Genetic studies in mouse revealed that transcription factor Tfcp2l1 coordinates IC and PC development. Tfcp2l1 induces the expression of IC specific genes, including specific H+-ATPase subunits and Jag1. Jag1 in turn, initiates Notch signaling in PCs but inhibits Notch signaling in ICs. Tfcp2l1 inactivation deletes ICs, whereas Jag1 inactivation results in the forfeiture of discrete IC and PC identities. Thus, Tfcp2l1 is a critical regulator of IC-PC patterning, acting cell-autonomously in ICs, and non-cell-autonomously in PCs. As a result, Tfcp2l1 regulates the diversification of cell types which is the central characteristic of 'salt and pepper' epithelia and distinguishes the collecting duct from all other nephron segments.