Inflammatory cell function during infection
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Monocytes and neutrophils are dominant cell populations recruited from the blood to sites of infection and injury. Exploring the function of these cells and how their activities are instructed in diverse tissue microenvironments is critical to improved understanding of inflammatory processes.
Using cutting-edge cellular and molecular techniques, this group employs well-characterised infections in tandem with patient samples to probe the full-spectrum of activation of these cell types with particular focus on the gastrointestinal tract.
Previously, Dr Grainger identified an unappreciated mechanism by which monocytes are able to take on regulatory features and directly modulate neutrophil activation. In particular, he found that during acute gastrointestinal infection monocytes produce the lipid mediator prostaglandin E2(PGE2) that plays a critical role in limiting highly pathologic neutrophil activation and prevents life-threatening gastrointestinal inflammation.
This activity was specific to the gastrointestinal tract and was in part dependent upon signals derived from the abundant commensal flora. This finding is of high clinical relevance as commonly used non-steroidal anti-inflammatory drugs (NSAIDs) act by limiting cyclooxygenase (COX) activity, a rate-limiting enzyme in PGE2 production.
Based on this finding, the major current goal of this group's studies is to understand how such novel regulatory features are acquired. Much research is currently focussed on understanding how tissue specific signals, such as those from the commensal flora, influence the function of recruited cell populations.
During gut infection, we have unexpectedly found that signals released systemically are needed to prime inflammatory cells during differentiation in order to induce regulatory capacity. Thus, inflammatory cells acquire regulatory functions towards gut bacteria prior to exit from the bone marrow.
This sheds light on a poorly explored process of inflammatory cell differentiation during infection in which systemic signals instruct eventual function toward local cues in tissue.
Improved mechanistic understanding of how systemic and local cues act in tandem to instruct inflammatory cell function could inform development of novel therapeutic strategies to treat diseases in which aberrant monocyte and neutrophil function is implicated, including inflammatory bowel diseases (IBD) and certain cancers