Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development.

Obesity-induced chronic liver inflammation is a hallmark of nonalcoholic steatohepatitis (NASH)-an aggressive form of nonalcoholic fatty liver disease. However, it remains unclear how such a low-grade, yet persistent, inflammation is sustained in the liver. Here, we show that the macrophage phagocytic receptor TREM2, induced by hepatocyte-derived sphingosine-1-phosphate, was required for efferocytosis of lipid-laden apoptotic hepatocytes and thereby maintained liver immune homeostasis. However, prolonged hypernutrition led to the production of proinflammatory cytokines TNF and IL-1ß in the liver to induce TREM2 shedding through ADAM17-dependent proteolytic cleavage. Loss of TREM2 resulted in aberrant accumulation of dying hepatocytes, thereby further augmenting proinflammatory cytokine production. This ultimately precipitated a vicious cycle that licensed chronic inflammation to drive simple steatosis transition to NASH. Therefore, impaired macrophage efferocytosis is a previously unrecognized key pathogenic event that enables chronic liver inflammation in obesity. Blocking TREM2 cleavage to restore efferocytosis may represent an effective strategy to treat NASH.

Relationship between central corneal thickness and retinal nerve fiber layer thickness in ocular hypertensive patients.

PURPOSE: To examine the relationship between retinal nerve fiber layer (RNFL) measurements obtained using scanning laser polarimetry with variable corneal compensation and corneal thickness measurements in ocular hypertension (OHT) patients. DESIGN: Observational cross-sectional study. SUBJECTS: The study included 1 eye each from 44 OHT patients and 48 healthy subjects, all of similar age. All subjects had normal optic discs and normal standard automated perimetry (SAP) visual fields. Ocular hypertension patients had intraocular pressure (IOP) measurements higher than 22 mmHg. METHODS: All patients underwent imaging with the GDx VCC (Laser Diagnostic Technologies, Inc., San Diego, CA) scanning laser polarimeter. We examined the relationship between GDx VCC RNFL measurements and central corneal thickness, a risk factor for development of visual field loss among OHT patients. We also examined the relationship of GDx VCC measurements and age, IOP, SAP pattern standard deviation, and vertical cup-to-disc ratio. MAIN OUTCOME MEASURES: Central corneal thickness (CCT) and GDx VCC RNFL thickness parameters. RESULTS: Central corneal thickness measurements in OHT patients were significantly higher than those in healthy subjects (575+/-30 microm vs. 555+/-32 microm; P = 0.002). Higher GDx VCC parameter nerve fiber indicator (NFI) scores, indicating thinner RNFL, were correlated significantly with thinner CCT measurements in OHT patients (r = -0.502; P = 0.001). Ocular hypertension patients with thinner corneas (n = 22; mean CCT, 553+/-21 microm) had significantly higher NFI scores than OHT patients with thicker corneas (n = 22; mean CCT, 598+/-18 microm) and healthy control subjects (NFI mean +/- standard deviation, 26.9+/-9.5, 20.7+/-9.8, and 19.7+/-7.0, respectively; P = 0.004, analysis of variance). The NFI values were not significantly different between OHT patients with thicker corneas and healthy subjects. In multivariate analysis, only age and CCT measurement were associated significantly with GDx VCC RNFL measurements in OHT eyes. CONCLUSIONS: Ocular hypertension patients with thinner corneas had significantly thinner RNFL than OHT patients with thicker corneas and healthy control subjects. These findings support the notion that RNFL defects as assessed by the GDx VCC may represent early glaucomatous damage in OHT eyes.