Selective Targeting of Tumour Necrosis Factor Receptor 1 Induces Stable Protection from Crohn's-Like Ileitis in TNFΔARE Mice.

BACKGROUND AND AIMS: Crohn's disease is a debilitating chronic inflammatory disorder of the mammalian gastrointestinal tract. Current interventions using anti-tumour necrosis factor [anti-TNF] biologics show long-term benefit in only half of patients. This study focused on the role of the TNF receptor 1 [TNFR1] in pathogenesis in a TNF-driven model of ileitis. METHODS: We studied TNFΔAU-rich element [ARE]/+ [TNFdARE] mice, which develop progressive ileitis similar to Crohn's ileitis. Histopathological analysis and gene expression profiling were used to characterize disease progression from 5 to 16 weeks. Mice with TNFR1 hemizygosity [TNFdARE/R1het] allowed us to assess gene dosage effects. Transcriptional profiling established inflection points in disease progression; inflammatory gene expression increased at 8 weeks with a plateau by 10 weeks, so these were selected as endpoints of treatment using the TNF biologic infliximab and the TNFR1-specific XPro1595. Differences in recruitment of cells in the lamina propria were assessed using flow cytometry. RESULTS: TNFdARE/R1het mice displayed stable long-term protection from disease, associated with decreased recruitment of CD11bhiF4/80lo monocytes and CD11bhiLy6Ghi neutrophils, suggesting an important role of TNFR1 signalling in pathogenesis, and indicating potential benefit from TNFR1-specific intervention. Treatment with infliximab and XPro1595 both showed a similar impact on disease in TNFdARE mice. Importantly, these beneficial effects were greatly surpassed by hemizygosity at the TNFR1 locus. CONCLUSIONS: Treatment with either infliximab or XPro1595 produced moderate protection from ileitis in TNFdARE mice. However, hemizygosity at the TNFR1 locus in TNFdARE mice showed far better protection, implicating TNFR1 signalling as a key mediator of TNF-driven disease.

Salton Sea aerosol exposure in mice induces a pulmonary response distinct from allergic inflammation.

In communities surrounding the Salton Sea, high rates of asthma are associated with high aerosol dust levels. However, the Salton Sea itself may play an additional role in pulmonary health. Therefore, to investigate a potential role of the Salton Sea on pulmonary health, we exposed mice to aerosolized Salton Sea water for 7 days and assessed tissue responses, including cellular infiltration and gene expression changes. For reference, mice were also exposed to aerosolized fungal allergen (Alternaria sp.) and Pacific Ocean aerosols. Exposure to aerosolized Alternaria sp. induced dramatic allergic inflammation, including neutrophil and eosinophil recruitment to the bronchoalveolar lavage fluid (BALF) and lung tissue. By contrast, Salton Sea "spray" induced only B cell recruitment to the lung tissue without increased inflammatory cell numbers in BALF. However, there were consistent gene expression changes suggestive of an inflammatory response. The response to the Salton Sea spray was notably distinct from the response to Pacific Ocean water, which induced some B cell recruitment but without an inflammatory gene expression profile. Our studies suggest that soluble components in Salton Sea water promote induction of a unique inflammation-associated response, though any relationship to asthma remains to be explored.