Inflammasomes are large macromolecular signaling complexes that control the proteolytic activation of two highly proinflammatory IL-1 family cytokines IL-1β and IL-18. that NLRP3 inflammasome activation may also be Iguratimod involved in acute lung inflammation after Iguratimod viral infection and during progression of several chronic pulmonary diseases including idiopathic pulmonary fibrosis chronic obstructive pulmonary disease and asthma. Here we review the most recent contributions to our understanding of the regulatory mechanisms controlling activation of the NLRP3 inflammasome and discuss the contribution of the NLRP3 inflammasome to the pathology of lung diseases. CME Accreditation Statement: This activity (“ASIP 2014 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity (“ASIP 2014 AJP CME Program in Pathogenesis”) for a maximum of 48 by immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors induces Syk activation Iguratimod and signaling resulting in formation of the NLRP3 inflammasome as well as synthesis of its substrate pro-IL-1β.47 In addition Lu et?al48 recently reported that protein kinase R (PKR) directly interacts with NLRP1 NLRP3 NLRC4 and AIM2 and that genetic ablation of the kinase domain of this protein severely impairs inflammasome-induced caspase-1 cleavage and IL-1β secretion. Given that PKR appears to be required for activation of several inflammasomes placement of this protein kinase upstream of these receptors is unlikely because this would remove the ligand specificity of their activation. More recent findings in macrophages reported no dependence on PKR during NLRP3 inflammasome activation.49 The reason for these discrepancies remains unclear and further studies need to be conducted to confirm a role for this protein kinase in NLRP3 activation. The kinase activity of TGF-β-activated kinase 1 (TAK1) also appears to play a role in NLRP3 activation because treatment of macrophages with a specific TAK1 inhibitor (5Z-7-oxozeaenol) blocks NLRP3 inflammasome activation independent of its ability to?inhibit TLR-induced NFκB responses.50 Interestingly TAK1 activation after intracellular Ca2+ mobilization has also been shown to be required for NLRP3 activation under conditions of cellular perturbation induced by cell swelling.51 Taken together the findings on Syk PKR and TAK1 raise the possibility that activation of an upstream protein kinase may potentially regulate the phosphorylation status of NLRP3 and its ability to form a functional inflammasome. Indeed a phosphorylation event has been shown to be critical for the function of the NLRC4 inflammasome.11 52 A single phosphorylation site at Ser533 by protein kinase Cδ (PKCδ) was identified by affinity purification and subsequent mass spectrometry Iguratimod of a tagged version of NLRC4 from infection. Macrophages infected by activate the NLRP3 inflammasome resulting in secretion of IL-18 which can subsequently stimulate the production of IFN-γ from T cells or natural killer cells. In turn IFN-γ can activate IFNGR on macrophages to stimulate NO production and the nitrosylation of NLRP3 thus preventing further NLRP3 activation.53 NLRP3 Foxd1 Expression in the Lung Most studies on the regulation and function of inflammasomes have been performed on murine bone marrow-derived macrophages or DCs. As noted above the inflammasomes likely play Iguratimod important roles in mediating an antimicrobial response in tissues. In addition chronic activation of inflammasomes in tissue-resident immune cells or even stromal cells could contribute to pathology such as chronic inflammation or fibrotic responses. An examination across murine tissues found mRNA to be most highly expressed in the spleen and next highest in the lung.55 The high expression of NLRP3 in the lung was attributed to the large amount of immune cells that populate this organ. Indeed alveolar macrophages comprise more than 90% of cells obtained from the bronchoalveolar lavage (BAL) fluid of na?ve mice.56 Alveolar macrophages express.