Interferon regulatory aspect 5 (IRF5) is a key transcription factor involved

Interferon regulatory aspect 5 (IRF5) is a key transcription factor involved in the control of the expression of pro-inflammatory cytokine and responses to contamination, however its role in regulating pulmonary immune responses to allergen is unknown. Th2-driven disease, many T-cell directed therapies have not been effective in clinical trials1,2. The lack of effective therapies for some types of asthma might reflect the poor understanding of the specific immunological pathways that lead to the disease. Interferon regulatory factor 5 (IRF5) is usually a key transcription factor involved in the control of the expression of pro-inflammatory cytokine responses to microbial contamination and type I interferon responses to viral contamination 3. IRF5 mRNA expression is usually increased in response to IFN-g and GM-CSF 4, whereas activation of IRF5 protein occurs in response to immune signaling pathways, such as downstream of TLRs etc, via post-translational modifications such as phosphorylation and ubiqutination 5. Polymorphisms in the gene encoding IRF5 PIK-75 that lead to higher mRNA expression are associated with many autoimmune diseases, such as rheumatoid arthritis6, Sjogrens syndrome7, systemic lupus erythematosus8, multiple sclerosis7 and inflammatory bowel disease9. Emerging genetic studies have Rabbit polyclonal to ZNF75A. provided evidence that implicates IRF5 in the pathogenesis of allergic disease. Wang recognized a common IRF5 haplotype to be associated with asthma and the severity of asthmatic symptoms and furthermore, the risk associated with IRF5 was found to be reverse in direction to those for autoimmune disorders 10. Recently, we exhibited that IRF5 is critical in establishing inflammatory macrophage phenotypes involved in the positive regulation of Th1/Th17 associated mediators, such as IL-1, IL12, IL-23 and TNF and the harmful legislation of Th2 associated-mediators, such as for example IL-10 3,4. Macrophages will be the many abundant immune-cell type PIK-75 within the lung environment under homeostatic circumstances and are as a result strategically positioned to regulate the innate protection from the airways 11,12. Two defined populations of macrophages in the lung are seen as a unique features and properties 13. Alveolar macrophages (AMs) can be found in in the airway lumen and so are seen as a high appearance of Compact disc11c but absence Compact disc11b appearance 14. Interstitial macrophages (IMs) have a home in the lung parenchyma, exhibit high levels of CD11b, low levels of CD11c and have been shown to control endotoxin-induced airway swelling 15. As PIK-75 a critical component of pulmonary immunity, alveolar macrophages are tightly controlled in order to preserve homeostasis; however, the molecular mechanisms by which this occurs are not well understood. We find that PIK-75 macrophages are the predominant IRF5-expressing cell type in the pulmonary compartment under homeostatic conditions. The absence of IRF5 during exposure to the clinically relevant allergen, house dust mite (HDM), resulted in improved airway hyper-responsiveness and sensitive inflammation, concomitant with elevated manifestation of extracellular matrix molecules and collagen deposition. Significantly, adoptive transfer of IRF5-deficient alveolar macrophages into the WT milieu was adequate to drive airway hyper-reactivity, actually in the absence of antigen activation. Conversely, over-expression of IRF5 resulted in ablated AHR, diminished eosinophilia and decreased type-2 cytokine production. These data determine IRF5-expressing macrophages as a key component of the immune defence of the airways. Manipulation of IRF5 activity in the lung could therefore be a viable strategy for the redirection of pulmonary immune responses and thus, the treatment of lung disorders. Results IRF5 deficiency prospects to augmented Type 2 reactions in the lung after HDM exposure In order to determine the part of IRF5 in regulating the pulmonary environment, we 1st revealed PIK-75 mice to the aeroallergen, house dust mite (HDM), instilled directly into the airways (Fig. 1A). Ablation of IRF5 experienced a profound effect on airway function, since IRF5-/- mice were hyper-responsive to.