Inflammation is associated with development of atherosclerosis, and cholesterol crystals (CC) have long been recognized as a hallmark of atherosclerotic lesions. CC appear early in the atheroma development and trigger inflammation by NLRP3 inflammasome activation. In this study we hypothesized whether CC employ the complement system to activate the inflammasome-caspase-1 leading to release of mature IL-1β, and if complement activation regulates CC-induced cytokine production. We here describe that CC activated both the classical and alternative complement pathways and C1q was found to be crucial for the activation. CC employed C5a in the release of a number of cytokines in whole blood, including IL-1β and TNF. CC induced minimal amounts of cytokines in C5-deficient whole blood, until reconstituted with C5. Furthermore, C5a and TNF in combination acted as a potent primer for CC-induced IL-1β release by increasing IL-1β transcripts. CC-induced complement activation resulted in up-regulation of Complement receptor 3 (CD11b/CD18) leading to phagocytosis of CC. Also, CC mounted a complement-dependent production of reactive oxygen species and active caspase-1. We conclude that CC employs the complement system to induce cytokines and activate the inflammasome-caspase-1 by regulating several cellular responses in human monocytes. In light of this, complement inhibition might be an interesting therapeutic approach for treatment of atherosclerosis.

Two functions have been assigned to properdin; stabilization of the alternative convertase, C3bBb, is well accepted, whereas the role of properdin as pattern recognition molecule is controversial. The presence of nonphysiological aggregates in purified properdin preparations and experimental models that do not allow discrimination between the initial binding of properdin and binding secondary to C3b deposition is a critical factor contributing to this controversy. In previous work, by inhibiting C3, we showed that properdin binding to zymosan and Escherichia coli is not a primary event, but rather is solely dependent on initial C3 deposition. In the present study, we found that properdin in human serum bound dose-dependently to solid-phase myeloperoxidase. This binding was dependent on C3 activation, as demonstrated by the lack of binding in human serum with the C3-inhibitor compstatin Cp40, in C3-depleted human serum, or when purified properdin is applied in buffer. Similarly, binding of properdin to the surface of human umbilical vein endothelial cells or Neisseria meningitidis after incubation with human serum was completely C3-dependent, as detected by flow cytometry. Properdin, which lacks the structural homology shared by other complement pattern recognition molecules and has its major function in stabilizing the C3bBb convertase, was found to bind both exogenous and endogenous molecular patterns in a completely C3-dependent manner. We therefore challenge the view of properdin as a pattern recognition molecule, and argue that the experimental conditions used to test this hypothesis should be carefully considered, with emphasis on controlling initial C3 activation under physiological conditions.

Background Although electrolyte imbalances (EIs) are common in the emergency department (ED), few studies have examined the occurrence of such conditions in an unselected population. Objectives To investigate the frequency of EI among adult patients who present to the ED, with regards to type and severity, and the association with age and sex of the patient, hospital length of stay (LOS), readmission, and mortality. Methods A retrospective cohort study. All patients ≥ 18 years referred for any reason to the ED between January 1, 2010, and December 31, 2015, who had measured blood electrolytes were included. In total, 62 991 visits involving 31 966 patients were registered. Results EIs were mostly mild, and the most common EI was hyponatremia (glucose-corrected) (24.6%). Patients with increasing severity of EI had longer LOS compared with patients with normal electrolyte measurements. Among all admitted patients, there were 12928 (20.5%) readmissions within 30 days from discharge during the study period. Hyponatremia (glucose-corrected) was associated with readmission, with an adjusted odds ratio (OR) of 1.25 (95% CI, 1.18–1.32). Hypomagnesemia and hypocalcemia (albumin-corrected) were also associated with readmission, with ORs of 1.25 (95% CI, 1.07–1.45) and 1.22 (95% CI, 1.02–1.46), respectively. Dysnatremia, dyskalemia, hypercalcemia, hypermagnesemia, and hyperphosphatemia were associated with increased in-hospital mortality, whereas all EIs except hypophosphatemia were associated with increased 30-day and 1-year mortality. Conclusions EIs were common and increasing severity of EIs was associated with longer LOS and increased in-hospital, 30-days and 1-year mortality. EI monitoring is crucial for newly admitted patients, and up-to-date training in EI diagnosis and treatment is essential for ED physicians.