Inflammatory Cell Function during Infection
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 my group employs well-characterized 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, I identified an unappreciated mechanism by which monocytes are able to take on regulatory features and directly modulate neutrophil activation. In particular, I 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 my groups’ 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.
Askenase MH, Han SJ, Byrd AL, Morais da Fonseca D, Bouladoux N, Wilhelm C, Konkel JE, Hand TW, Lacerda-Queiroz N, Su XZ, Trinchieri G, Grainger JR* and Belkaid Y. (2015) Bone-Marrow-Resident NK Cells Prime Monocytes for Regulatory Functions during Infection. Immunity. 42(6): 1130-42. *Corresponding author.
Molloy MJ*, Grainger JR*, Bouladoux N*, Hand TW, Koo LY, Naik S, Quinones M, Dzutsev AK, Gao JL, Trinchieri G, Murphy PM, Belkaid Y. (2013) Intraluminal containment of commensal outgrowth in the gut during infection-induced dysbiosis. Cell Host & Microbe. 14(3): 318-28. *Primary authors contributed equally to this work.
Grainger JR, Wohlfert EA, Fuss IJ, Bouladoux N, Askenase MH, Legrand F, Koo LY, Brenchley JM, Fraser ID, Belkaid Y. (2013) Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection. Nature Medicine. 19(6): 713-21.
Carpenter AC*, Grainger JR*, Xiong Y*, Kanno Y, Chu HH, Wang L, Naik S, dos Santos L, Wei L, Jenkins MK, O’Shea JJ, Belkaid Y, Bosselut R. (2012) The transcription factors Thpok and LRF are necessary and partly redundant for T helper cell differentiation. Immunity. 37(4): 622-33. *Primary authors contributed equally to this work.
Grainger JR, Smith KA, Hewitson JP, McSorley HJ, Harcus Y, Filbey KJ, Finney CA, Greenwood EJ, Knox DP, Wilson MS, Belkaid Y, Rudensky AY, Maizels RM. (2010) Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-b pathway. The Journal of Experimental Medicine. 207(11): 2331-41.