Retention of the NLRP3 Inflammasome-Primed Neutrophils in the Bone Marrow Is Essential for Myocardial Infarction-Induced Granulopoiesis.

BACKGROUND: Acute myocardial infarction (MI) results in overzealous production and infiltration of neutrophils to the ischemic heart. This is mediated in part by granulopoiesis induced by the S100A8/A9-NLRP3-IL-1ß signaling axis in injury-exposed neutrophils. Despite the transcriptional upregulation of the NLRP3 (Nod Like Receptor Family Pyrin Domain-Containing 3) inflammasome and associated signaling components in neutrophils, the serum levels of IL-1ß (interleukin-1ß), the effector molecule in granulopoiesis, were not affected by MI, suggesting that IL-1ß is not released systemically. We hypothesize that IL-1ß is released locally within the bone marrow (BM) by inflammasome-primed and reverse-migrating neutrophils. METHODS: Using a combination of time-dependent parabiosis and flow cytometry techniques, we first characterized the migration patterns of different blood cell types across the parabiotic barrier. We next induced MI in parabiotic mice by permanent ligation of the left anterior descending artery and examined the ability of injury-exposed neutrophils to permeate the parabiotic barrier and induce granulopoiesis in noninfarcted parabionts. Last, using multiple neutrophil adoptive and BM transplant studies, we studied the molecular mechanisms that govern reverse migration and retention of the primed neutrophils, IL-1ß secretion, and granulopoiesis. Cardiac function was assessed by echocardiography. RESULTS: MI promoted greater accumulation of the inflammasome-primed neutrophils in the BM. Introducing a time-dependent parabiotic barrier to the free movement of neutrophils inhibited their ability to stimulate granulopoiesis in the noninfarcted parabionts. Previous priming of the NLRP3 inflammasome is not a prerequisite, but the presence of a functional CXCR4 (C-X-C-motif chemokine receptor 4) on the primed-neutrophils and elevated serum S100A8/A9 levels are necessary for homing and retention of the reverse-migrating neutrophils. In the BM, the primed-neutrophils secrete IL-1ß through formation of gasdermin D pores and promote granulopoiesis. Pharmacological and genetic strategies aimed at the inhibition of neutrophil homing or release of IL-1ß in the BM markedly suppressed MI-induced granulopoiesis and improved cardiac function. CONCLUSIONS: Our data reveal a new paradigm of how circulatory cells establish a direct communication between organs by delivering signaling molecules (eg, IL-1ß) directly at the sites of action rather through systemic release. We suggest that this pathway may exist to limit the off-target effects of systemic IL-1ß release.

The association between retinal vessel diameter and retinal nerve fiber layer thickness in asymmetric normal tension glaucoma patients.

PURPOSE: The aim of this study was to evaluate the associations between retinal vessel diameter and retinal nerve fiber layer (RNFL) thickness in patients with normal tension glaucoma (NTG). METHODS: This study included 67 untreated patients with asymmetric NTG, with no evidence of glaucoma in the contralateral eyes, and 48 age- and sex-matched normal control subjects. We included patients from 20 to 70 years of age who had no history of hypertension, diabetes, or other vascular diseases. All subjects underwent detailed eye examinations that included red-free photography, stereoscopic optic disc photography, automated perimetry, and measurement of RNFL thickness with optical coherence tomography. We compared RNFL thicknesses, temporal retinal arteriolar diameters (TRAD), and temporal retinal venular diameters (between quadrants with and without RNFL defects) with computer-assisted imaging software. RESULTS: The mean diameter of the temporal retinal vessels in the quadrants with RNFL defects were significantly smaller in patients with NTG than in those with quadrants without RNFL defects (P < 0.001) and in control subjects (P < 0.001). TRADs were correlated with RNFL defects and RNFL thicknesses (P < 0.05) in binary logistic regression analysis and in multiple linear regression analysis (P < 0.001). There were no statistically significant differences between vessel diameters in control subjects and those in nondefective quadrants of the affected NTG eyes or the unaffected eyes of patients with NTG. CONCLUSIONS: Our results show that narrower retinal vessels are found in areas of RNFL defects. Considering previous reports and our analysis, this is likely due to the decreased demand for retinal blood flow in damaged areas of the retina.