title: Common genetic variations in the NALP3 inflammasome are associated with delayed apoptosis of human neutrophils.
abstract: BACKGROUND
  Neutrophils are key-players in the innate host defense and their programmed cell death and removal are essential for efficient resolution of inflammation. These cells recognize a variety of pathogens, and the NOD-like receptors (NLRs) have been suggested as intracellular sensors of microbial components and cell injury/stress. Some NLR will upon activation form multi-protein complexes termed inflammasomes that result in IL-1β production. NLR mutations are associated with auto-inflammatory syndromes, and our previous data propose NLRP3 (Q705K)/CARD-8 (C10X) polymorphisms to contribute to increased risk and severity of inflammatory disease by acting as genetic susceptibility factors. These gene products are components of the NALP3 inflammasome, and approximately 6.5% of the Swedish population are heterozygote carriers of these combined gene variants. Since patients carrying the Q705K/C10X polymorphisms display leukocytosis, the aim of the present study was to find out whether the inflammatory phenotype was related to dysfunctional apoptosis and impaired clearance of neutrophils by macrophages.
  
  
  RESULTS
  Patients carrying the Q705K/C10X polymorphisms displayed significantly delayed spontaneous as well as microbe-induced apoptosis compared to matched controls. Western blotting revealed increased levels and phosphorylation of Akt and Mcl-1 in the patients' neutrophils. In contrast to macrophages from healthy controls, macrophages from the patients produced lower amounts of TNF; suggesting impaired macrophage clearance response.
  
  
  CONCLUSIONS
  The Q705K/C10X polymorphisms are associated with delayed apoptosis of neutrophils. These findings are explained by altered involvement of different regulators of apoptosis, resulting in an anti-apoptotic profile. Moreover, the macrophage response to ingestion of microbe-induced apoptotic neutrophils is altered in the patients. Taken together, the patients display impaired turnover and clearance of apoptotic neutrophils, pointing towards a dysregulated innate immune response that influences the resolution of inflammation. The future challenge is to understand how microbes affect the activation of inflammasomes, and why this interaction will develop into severe inflammatory disease in certain individuals.
authors.affiliation: Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Blomgran
authors.forename: Veronika
authors.initials: V
authors.lastname: Patcha Brodin
authors.forename: Deepti
authors.initials: D
authors.lastname: Verma
authors.forename: Ida
authors.initials: I
authors.lastname: Bergström
authors.forename: Peter
authors.initials: P
authors.lastname: Söderkvist
authors.forename: Christopher
authors.initials: C
authors.lastname: Sjöwall
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Maria
authors.initials: M
authors.lastname: Lerm
authors.forename: Olle
authors.initials: O
authors.lastname: Stendahl
authors.forename: Eva
authors.initials: E
authors.lastname: Särndahl
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D015415:Biomarkers / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics; D018821:CD18 Antigens / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D061945:Caspase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D058847:Inflammasomes / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D011110:Polymorphism, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013211:Staphylococcus aureus / Q000502:physiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015415:Biomarkers; D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; D018821:CD18 Antigens; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D058847:Inflammasomes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases