NLRP11 is a pattern recognition receptor for bacterial lipopolysaccharide in the cytosol of human macrophages.

Endotoxin-bacterial lipopolysaccharide (LPS)-is a driver of lethal infection sepsis through excessive activation of innate immune responses. When delivered to the cytosol of macrophages, cytosolic LPS (cLPS) induces the assembly of an inflammasome that contains caspases-4/5 in humans or caspase-11 in mice. Whereas activation of all other inflammasomes is triggered by sensing of pathogen products by a specific host cytosolic pattern recognition receptor protein, whether pattern recognition receptors for cLPS exist has remained unclear, because caspase-4, caspase-5, and caspase-11 bind and activate LPS directly in vitro. Here, we show that the primate-specific protein NLRP11 is a pattern recognition receptor for cLPS that is required for efficient activation of the caspase-4 inflammasome in human macrophages. In human macrophages, NLRP11 is required for efficient activation of caspase-4 during infection with intracellular Gram-negative bacteria or upon electroporation of LPS. NLRP11 could bind LPS and separately caspase-4, forming a high-molecular weight complex with caspase-4 in HEK293T cells. NLRP11 is present in humans and other primates but absent in mice, likely explaining why it has been overlooked in screens looking for innate immune signaling molecules, most of which have been carried out in mice. Our results demonstrate that NLRP11 is a component of the caspase-4 inflammasome activation pathway in human macrophages.

The role of diffusion weighted imaging as supplement to dynamic contrast enhanced breast MRI: Can it help predict malignancy, histologic grade and recurrence?

RATIONALE AND OBJECTIVES: To evaluate the value of adding Diffusion Weighted Imaging (DWI) with Apparent Diffusion Coefficient (ADC) mapping to dynamic contrast enhanced (DCE-MRI) to distinguish benign from malignant pathology subtypes and tumor recurrence. METHOD AND MATERIALS: In this retrospective IRB approved study, 956 consecutive patients underwent bilateral breast MRI between 1/2015 and 12/2015, with 156 BIRADS 4, 5, or 6 lesions detected in 111 patients. DWI imaging at B0, B100, B600, B1000 was performed with DCE-MRI. Values for diffusion and ADC images were recorded by two fellowship-trained breast radiologists. Mean ADC and signal intensity (SI) values were correlated with histology, tumor grade, hormone receptors (ER, PR, and HER-2)and Oncotype DX scores, when available. p ≤ 0.05 was considered significant. RESULTS: Of 156 lesions, there were 59 (38%) benign lesions, 24 (15%) Ductal Carcinoma In-Situ, 47 (30%) Invasive Ductal Carcinoma (IDC), 15 (10%) Invasive Lobular Carcinoma (ILC) and 2 (2%) Mucinous carcinoma (MC), five (5%) mixed IDC and ILC, and four (4%) other, including tubular and rare types of malignancy. Mean ADC values for malignancy were significantly lower than for benign lesions (1085 ± 343 × 10-6 vs 1481 ± 276 × 10-6 mm2/s), which is highly predictive (area under curve = 0.82). In addition, tumors with PR negativity and Oncotype score ≥18 (intermediate to high risk for recurrence) demonstrated significantly lower ADC values. SI at B100 and B600 was helpful in distinguishing benign versus IDC. There was no significant correlation between ADC values and tumor grade or ER/HER2 status. CONCLUSION: ADC value is important factor in distinguishing malignancy, differentiating tumors with higher Oncotype score, and PR negativity. Therefore, it can be used as an important tool to assist appropriate treatment selection.