Search

Influenza A virus-specific (IAV-specific) T cell responses are important correlates of protection during primary and subsequent infections. The generation and maintenance of robust IAV-specific T cell responses relies on T cell interactions with dendritic cells (DCs). In this study, we explore the role of the nucleotide-binding domain leucine-rich repeat- containing receptor family member NLRC4 in modulating the DC phenotype during IAV infection. [Nlrc4.sup.-/-] mice had worsened survival and increased viral titers during infection, normal innate immune cell recruitment, and IAV-specific [CD8.sup.+] T cell responses, but severely blunted IAV-specific [CD4.sup.+] T cell responses compared with WT mice. The defect in the pulmonary IAV-specific [CD4.sup.+] T cell response was not a result of defective priming or migration of these cells in [Nlrc4.sup.-/-] mice but was instead due to an increase in [FasL.sup.+] DCs, resulting in IAV- specific [CD4.sup.+] T cell death. Together, our data support a role for NLRC4 in regulating the phenotype of lung DCs during a respiratory viral infection and thereby influencing the magnitude of protective T cell responses., Introduction Influenza A virus (IAV) is a respiratory pathogen responsible for seasonal epidemics that can cause severe disease and death, most commonly in the very young, very old, and immunocompromised [...]

Introduction Influenza infects millions of people each year causing respiratory distress and death in severe cases. On average, 200,000 people annually are hospitalized in the United States for influenza related complications. Tissue inhibitor of metalloproteinase-1 (TIMP-1), a secreted protein that inhibits MMPs, has been found to be involved in lung inflammation. Here, we evaluated the role of TIMP-1 in the host response to influenza-induced lung injury. Methods Wild-type (WT) and Timp1-deficient (Timp1.sup.-/-) mice that were 8-12 weeks old were administered A/PR/8/34 (PR8), a murine adapted H1N1 influenza virus, and euthanized 6 days after influenza installation. Bronchoalveolar lavage fluid and lungs were harvested from each mouse for ELISA, protein assay, PCR, and histological analysis. Cytospins were executed on bronchoalveolar lavage fluid to identify immune cells based on morphology and cell count. Results WT mice experienced significantly more weight loss compared to Timp1.sup.-/- mice after influenza infection. WT mice demonstrated more immune cell infiltrate and airway inflammation. Interestingly, PR8 levels were identical between the WT and Timp1.sup.-/- mice 6 days post-influenza infection. Conclusion The data suggest that Timp1 promotes the immune response in the lungs after influenza infection facilitating an injurious phenotype as a result of influenza infection., Author(s): Jenieke R. Allen [sup.1] , Lingyin Ge [sup.1] , Ying Huang [sup.1] , Rena Brauer [sup.1] , Tanyalak Parimon [sup.1] , Suzanne L. Cassel [sup.1] , Fayyaz S. Sutterwala [...]

Members of the NLR family can assemble inflammasome complexes with the adaptor protein ASC and caspase-1 that result in the activation of caspase-1 and the release of IL-1β and IL-18. Although the NLRC4 inflammasome is known to have a protective role in tumorigenesis, there is an increased appreciation for the inflammasome-independent actions of NLRC4. Here, we utilized a syngeneic subcutaneous murine model of B16F10 melanoma to explore the role of NLRC4 in tumor suppression. We found that NLRC4-deficient mice exhibited enhanced tumor growth that was independent of the inflammasome components ASC and caspase-1. Nlrc4 expression was critical for cytokine and chemokine production in tumor-associated macrophages and was necessary for the generation of protective IFN-γ-producing [CD4.sup.+] and [CD8.sup.+] T cells. Tumor progression was diminished when WT or caspase-1-deficient, but not NLRC4-deficient, macrophages were coinjected with B16F10 tumor cells in NLRC4-deficient mice. Finally, examination of human primary melanomas revealed the extensive presence of [NLRC4.sup.+] tumor-associated macrophages. In contrast, there was a paucity of [NLRC4.sup.+] tumor-associated macrophages observed in human metastatic melanoma, supporting the concept that NLRC4 expression controls tumor growth. These results reveal a critical role for NLRC4 in suppressing tumor growth in an inflammasome-independent manner., Introduction Melanoma is one ofthe deadliest forms of skin cancer, and advanced cases of melanoma are especially hard to treat due to limited therapeutic options (1, 2). Increased risk of [...]

Inhalation of crystalline silica and asbestos is known to cause the progressive pulmonary fibrotic disorders silicosis and asbestosis, respectively. Although alveolar macrophages are believed to initiate these inflammatory responses, the mechanism by which this occurs has been unclear. Here we show that the inflammatory response and subsequent development of pulmonary fibrosis after inhalation of silica is dependent on the Nalp3 inflammasome. Stimulation of macrophages with silica results in the activation of caspase-1 in a Nalp3-dependent manner. Macrophages deficient in components of the Nalp3 inflammasome were incapable of secreting the proinflammatory cytokines interleukin (IL)-1[beta] and IL-18 in response to silica. Similarly, asbestos was capable of activating caspase-1 in a Nalp3-dependent manner. Activation of the Nalp3 inflammasome by silica required both an efflux of intracellular potassium and the generation of reactive oxygen species. This study demonstrates a key role for the Nalp3 inflammasome in the pathogenesis of pneumoconiosis. asbestosis | NLRP3 | caspase-1 | interleukin-1[beta]