Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2018-2019)

An important function of the host immune system is to initiate an inflammatory response that is required to control foreign insults and initiate tissue repair. The inflammatory process is normally self-limiting and regulated in order to avoid collateral self-damage. A dysregulation of inflammation results in excessive and persistent inflammation. A characteristic feature of uncontrolled inflammation is elevated expression of certain cytokines collectively known as proinflammatory cytokines. Myeloid immune cells (particularly macrophages and neutrophils) play important roles in inflammation via their production of inflammatory mediators including cytokines. The molecular mechanisms controlling inflammation have not been fully delineated.
Recently, my group showed that Diminazene aceturate (Berenil), which is an aromatic diamidine, inhibits IL-1, IL-6, IL-12 and TNF production by macrophages in vivo and in vitro following stimulation with Trypanosoma congolense, lipopolysaccharide (LPS) and CpG. This global suppressive effect was due to downregulation of phosphorylation of mitogen-activated protein kinases (MAPKs, including ERK, p38 and JNK), signal transducer and activator of transcription (STAT) proteins (STAT1 and STAT3) and NFκB p65 subunit, which are key signaling molecules and transcription factors involved in the production of proinflammatory cytokines. Berenil also increases neutrophil numbers in lungs, blood and peritoneal lavage fluids following LPS challenge. The molecular mechanisms through which Berenil mediates increased neutrophil survival and/or number is unknown.

Hypothesis: Berenil blocks proinflammatory cytokine production in macrophages by altering expression of suppressors of cytokine singling and regulating neutrophil survival.

The overarching goal of the current renewal application is to identify the cellular and molecular mechanisms by which Berenil regulates inflammatory cytokine responses in macrophages and neutrophils in vitro and in vivo. The objectives are: (i) to investigate the mechanisms through which Berenil suppresses proinflammatory cytokine production in macrophages (Theme 1) and (ii) determine whether Berenil treatment increases neutrophil survival, recruitment or/or mobilization from the bone marrow by assessing for markers of apoptosis in neutrophils from various tissue sites (Theme 2).

The proposed studies will establish the mechanistic processes involved in the anti-inflammatory properties of Berenil. The long-term vision is to have a broad and in-depth understanding of mechanisms that regulate inflammatory responses, which may reveal novel ways of targeting inflammatory conditions. The novelty of the research project and the cutting edge technologies involved will continue to create a rich environment for the training of HQP (2-3 graduate and 5 undergraduate students).