Anti-CD68 monoclonal antibody, clone FE2 [R-PE]

Neuroinflammation contributes to the pathogenesis of early brain injury induced by subarachnoid hemorrhage (SAH). Previous reports have demonstrated that triggering receptor expressed on myeloid cells 1 (TREM-1) regulates inflammatory response caused by ischemic stroke or myocardial infarction. However, whether TREM-1 could modulate neuroinflammation after SAH remains largely unknown. Here, using a mouse model of SAH, we found that the expression of TREM-1 was mainly located in microglia cells and increased to peak at 24 h following SAH. Then, TREM-1 antagonist or mimic was intranasally administrated to investigate its effect on SAH. TREM-1 inhibition with LP17 improved neurological deficits, mitigated brain water content, and preserved brain-blood barrier integrity 24 h after SAH, whereas recombinant TREM-1, a mimic of TREM-1, deteriorated these outcomes. In addition, LP17 administration restored long-term sensorimotor coordination and cognitive deficits. Pharmacological blockade of TREM-1 reduced TUNEL-positive and FJC-positive neurons, and CD68-stained microglia in ipsilateral cerebral cortex. Neutrophil invasion was inhibited as protein level of myeloperoxidase (MPO), and MPO-positive cells were both decreased. Moreover, we found that LP17 treatment ameliorated microglial pyroptosis by diminishing levels of N-terminal fragment of GSDMD (GSDMD-N) and IL-1 beta production. Mechanistically, both in vivo and in vitro, we depicted that TREM-1 can trigger microglial pyroptosis via activating NLRP3 inflammasome. In conclusion, our results revealed the critical role of TREM-1 in neuroinflammation following SAH, suggesting that TREM-1 inhibition might be a potential therapeutic approach for SAH.

OBJECTIVES This study prospectively evaluated endomyocardial biopsies in patients with heart failure with preserved ejection fraction (HFpEF) to identify histopathotogic phenotypes and their association with clinical characteristics. BACKGROUND Myocardial tissue analysis from a prospectively defined HFpEF cohort reflecting contemporary comorbidities is lacking. METHODS Patients with HFpEF (EF >= 50%) referred to the Johns Hopkins HFpEF Clinic between August 2014 and September 2018 were enrolled for right heart catheterization and endomyocardiat biopsy. Clinical features, echocardiography, hemodynamics, and tissue histology were determined and compared with controls (unused donor hearts) and HF with reduced EF (HFrEF). RESULTS Of the 108 patients enrolled, median age was 66 years (25th to 75th percentile: 57 to 74 years), 61% were women, 57% were African American, 62% had a previous HF hospitalization, median systolic blood pressure was 141 mm Hg (25th to 75th percentile: 125 to 162 mm Hg), body mass index (BMI) was 37 kg/m(2) (25th to 75th percentile: 32 to 45 kg/m(2)), and 97% were on a loop diuretic. Myocardial fibrosis and myocyte hypertrophy were often present (93% and 88%, respectively); however, mild in 71% with fibrosis and in 52% with hypertrophy. Monocyte infiltration (CD68-rcells/mm(2)) was greater in patients with HFpEF versus controls (60.4 cells/mm(2) [25th to 75th percentile: 36.8 to 97.8] vs. 32.1 cells/mm(2) [25th to 75th percentile: 22.3 to 59.2]; p = 0.02) and correlated with age and renal disease. Cardiac amytoidosis (CA) was diagnosed in 15 (14%) patients (HFpEF-CA: 7 patients with wild-type transthyretin amytoidosis (ATTR], 4 patients with hereditary ATTR, 3 patients with tight-chain amytoidosis, and 1 patient with AA (secondary) amytoidosis), of which 7 cases were unsuspected. Patients with HFpEF-CA were older, with tower BMI, higher left ventricular mass index, and higher N-terminal pro 8-type natriuretic peptide and troponin 1 levels. CONCLUSIONS In this large, prospective myocardial tissue analysis of HFpEF, myocardial fibrosis and hypertrophy were common, CD68+ inflammation was increased, and CA prevalence was 14%. Tissue analysis in HFpEF might improve precision therapies by identifying relevant myocardial mechanisms. (C) 2020 Published by Elsevier on behalf of the American College of Cardiology Foundation.