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aeruginosa  inflammasome  inner rod  inner  nlrc inflammasome  nlrc  protein  pseudomonas aeruginosa  rod protein  rod  sensing  thymic 
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Preview: International Immunology - Advance Access

International Immunology Advance Access

Published: Tue, 12 Sep 2017 00:00:00 GMT

Last Build Date: Tue, 12 Sep 2017 10:48:14 GMT


Autoimmunity associated with chemically induced thymic dysplasia


Autoimmune and inflammatory conditions are a frequent complication in patients with reduced numbers of T cells. Here, we describe a mouse model of thymic stromal dysplasia resulting in peripheral T cell lymphopenia. In Foxn1:CFP-NTR transgenic mice, the bacterial nitroreductase enzyme is expressed in thymic epithelial cells and converts the prodrug CB1954 into a cytotoxic agent. This strategy enables titratable and durable destruction of thymopoietic tissue in early embryogenesis. Our results indicate that the resulting low levels of thymic capacity for T cell production create a predisposition for the development of a complex autoimmune syndrome, chiefly characterized by inflammatory bowel disease and lymphocytic organ infiltrations. We conclude that the Foxn1:CFP-NTR transgenic mouse strain represents a suitable animal model to optimize established clinical protocols, such as thymus transplantation, to correct various forms of thymic dysplasia, and to explore novel treatment options.

The human NAIP-NLRC4-inflammasome senses the Pseudomonas aeruginosa T3SS inner-rod protein


While NLRC4-dependent sensing of intracellular Gram-negative pathogens such as Salmonella Typhimurium is a beneficial host response, NLRC4-dependent sensing of the Pseudomonas aeruginosa type 3 secretion system (T3SS) has been shown to be involved in pathogenicity. In mice, different pathogen-associated microbial patterns are sensed by the combination of the NLRC4-inflammasome with different members of neuronal apoptosis inhibitory protein (NAIPs). NAIP2 is involved in sensing PscI, an inner-rod protein of the P. aeruginosa T3SS. Surprisingly, only a single human NAIP (hNAIP) has been found in humans. Moreover, there is no description of NLRC4/hNAIP inflammasome recognition of T3SS inner-rod proteins in humans. Here, we show that the P. aeruginosa T3SS inner-rod protein PscI, and needle protein PscF are both sensed by the hNAIP/NLRC4-inflammasome in human macrophages and Peripheral Blood Mononuclear Cells from healthy donors, allowing caspase-1 and IL1-β maturation and resulting in a robust inflammatory response. TLR4 and TLR2 are involved in redundantly sensing these two T3SS components.