IL-33: Friend or foe in transplantation?

Several reports have highlighted the dichotomous nature of the Interleukin-33 (IL-33) system in cardiac and lung disease, where this cytokine can exert both protective effects and drive pro-inflammatory responses in a context-specific manner. This State-of-the-Art review focuses on preclinical mechanistic studies of the IL-33 system in development of allograft rejection in heart and lung transplantation. We address the scope of potential cellular sources of IL-33 and pathways for cellular release that may impact the study of this cytokine system in transplant models. We then highlight soluble IL-33 receptor as a biomarker in cardiac allograft rejection and detail preclinical models that collectively demonstrate a role for this cytokine in driving type-2 immune programs to protect cardiac allografts. We contrast this with investigation of IL-33 in lung transplantation, which has yielded mixed and somewhat conflicting results when comparing human studies with preclinical models, which have implicated the IL-33 system in both allograft tolerance and acceleration of chronic rejection. We summarize and interpret these results in aggregate and provide future directions for study of IL-33 in heart and lung transplantation.

Activator protein transcription factors coordinate human IL-33 expression from noncanonical promoters in chronic airway disease.

IL-33 is a cytokine central to type 2 immune pathology in chronic airway disease. This cytokine is abundantly expressed in the respiratory epithelium and increased in disease, but how expression is regulated is undefined. Here we show that increased IL33 expression occurs from multiple noncanonical promoters in human chronic obstructive pulmonary disease (COPD), and it facilitates production of alternatively spliced isoforms in airway cells. We found that phorbol 12-myristate 13-acetate (PMA) can activate IL33 promoters through protein kinase C in primary airway cells and lines. Transcription factor (TF) binding arrays combined with RNA interference identified activator protein (AP) TFs as regulators of baseline and induced IL33 promoter activity. ATAC-Seq and ChIP-PCR identified chromatin accessibility and differential TF binding as additional control points for transcription from noncanonical promoters. In support of a role for these TFs in COPD pathogenesis, we found that AP-2 (TFAP2A, TFAP2C) and AP-1 (FOS and JUN) family members are upregulated in human COPD specimens. This study implicates integrative and pioneer TFs in regulating IL33 promoters and alternative splicing in human airway basal cells. Our work reveals a potentially novel approach for targeting IL-33 in development of therapeutics for COPD.

Bacterial sepsis increases hippocampal fibrillar amyloid plaque load and neuroinflammation in a mouse model of Alzheimer's disease.

BACKGROUND: Sepsis, a leading cause for intensive care unit admissions, causes both an acute encephalopathy and chronic brain dysfunction in survivors. A history of sepsis is also a risk factor for future development of dementia symptoms. Similar neuropathologic changes are associated with the cognitive decline of sepsis and Alzheimer's disease (AD), including neuroinflammation, neuronal death, and synaptic loss. Amyloid plaque pathology is the earliest pathological hallmark of AD, appearing 10 to 20 years prior to cognitive decline, and is present in 30% of people over 65. As sepsis is also more common in older adults, we hypothesized that sepsis might exacerbate amyloid plaque deposition and plaque-related injury, promoting the progression of AD-related pathology. METHODS: We evaluated whether the brain's response to sepsis modulates AD-related neurodegenerative changes by driving amyloid deposition and neuroinflammation in mice. We induced polymicrobial sepsis by cecal ligation and puncture (CLP) in APP/PS1-21 mice, a model of AD-related ß-amyloidosis. We performed CLP or sham surgery at plaque onset (2 months of age) and examined pathology 2 months after CLP in surviving mice. RESULTS: Sepsis significantly increased fibrillar amyloid plaque formation in the hippocampus of APP/PS1-21 mice. Sepsis enhanced plaque-related astrocyte activation and complement C4b gene expression in the brain, both of which may play a role in modulating amyloid formation. CLP also caused large scale changes in the gut microbiome of APP/PS1 mice, which have been associated with a pro-amyloidogenic and neuroinflammatory state. CONCLUSIONS: Our results suggest that experimental sepsis can exacerbate amyloid plaque deposition and plaque-related inflammation, providing a potential mechanism for increased dementia in older sepsis survivors.