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Selected Publications

Cell, Volume 180, 2020

Enteric Nervous System-Derived IL-18 Orchestrates Mucosal Barrier Immunity

Mucosal barrier immunity is essential for the maintenance of the commensal microflora and combating invasive bacterial infection. Although immune and epithelial cells are thought to be the canonical orchestrators of this complex equilibrium, here, we show that the enteric nervous system (ENS) plays an essential and non-redundant role in governing the antimicrobial protein (AMP) response. Using confocal microscopy and single-molecule fluorescence in situ mRNA hybridization (smFISH) studies, we observed that intestinal neurons produce the pleiotropic cytokine IL-18. Strikingly, deletion of IL-18 from the enteric neurons alone, but not immune or epithelial cells, rendered mice susceptible to invasive Salmonella typhimurium (S.t.) infection. Mechanistically, unbiased RNA sequencing and single-cell sequencing revealed that enteric neuronal IL-18 is specifically required for homeostatic goblet cell AMP production. Together, we show that neuron-derived IL-18 signaling controls tissue-wide intestinal immunity and has profound consequences on the mucosal barrier and invasive bacterial killing.

Nature, Volume 573, 2019

Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity

Direct recognition of invading pathogens by innate immune cells is a critical driver of the inflammatory response. However, cells of the innate immune system can also sense their local microenvironment and respond to physiological fluctuations in temperature, pH, oxygen and nutrient availability, which are altered during inflammation. Although cells of the immune system experience force and pressure throughout their life cycle, little is known about how these mechanical processes regulate the immune response. Here we show that cyclical hydrostatic pressure, similar to that experienced by immune cells in the lung, initiates an inflammatory response via the mechanically activated ion channel PIEZO1. Mice lacking PIEZO1 in innate immune cells showed ablated pulmonary inflammation in the context of bacterial infection or fibrotic autoinflammation. Our results reveal an environmental sensory axis that stimulates innate immune cells to mount an inflammatory response, and demonstrate a physiological role for PIEZO1 and mechanosensation in immunity.

Nature, Volume 564, 2018

The translation of non-canonical open reading frames controls mucosal immunity

The annotation of the mammalian protein-coding genome is incomplete. Arbitrary size restriction of open reading frames (ORFs) and the absolute requirement for a methionine codon as the sole initiator of translation have constrained the identification of potentially important transcripts with non-canonical protein-coding potential. Here, using unbiased transcriptomic approaches in macrophages that respond to bacterial infection, we show that ribosomes associate with a large number of RNAs that were previously annotated as ‘non-protein coding’. Although the idea that such non-canonical ORFs can encode functional proteins is controversial, we identify a range of short and non-ATG-initiated ORFs that can generate stable and spatially distinct proteins. Notably, we show that the translation of a new ORF ‘hidden’ within the long non-coding RNA Aw112010 is essential for the orchestration of mucosal immunity during both bacterial infection and colitis. This work expands our interpretation of the protein-coding genome and demonstrates that proteinaceous products generated from non-canonical ORFs are crucial for the immune response in vivo. We therefore propose that the misannotation of non-canonical ORF-containing genes as non-coding RNAs may obscure the essential role of a multitude of previously undiscovered protein-coding genes in immunity and disease.

Cell, Volume 163, 2015

Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis

The intestinal mucosal barrier controlling the resident microbiome is dependent on a protective mucus layer generated by goblet cells, impairment of which is a hallmark of the inflammatory bowel disease Ulcerative Colitis. Here we show that IL-18 is critical in driving the pathologic breakdown of barrier integrity in a model of colitis. Deletion of Il18 or its receptor Il18r1 in intestinal epithelial cells (Δ/EC) conferred protection from colitis and mucosal damage in mice. In contrast, deletion of the IL-18 negative regulator Il18bp resulted in severe colitis associated with loss of mature goblet cells. Colitis and goblet cell loss were rescued in Il18bp−/−;Il18rΔ/EC mice, demonstrating that colitis severity is controlled at the level of IL-18 signaling in intestinal epithelial cells. IL-18 inhibited goblet cell maturation by regulating the transcriptional program instructing goblet cell development. These results inform on the mechanism of goblet cell dysfunction which underlies the pathology of Ulcerative Colitis.


Enteric Nervous System Derived IL-18 Orchestrates Mucosal Barrier Immunity. Cell. 2020 180(50-63). Jarret A*, Jackson R*#, Duizer C, Healy ME, Zhao J, Rone JM, Bielecki P, Sefik E, Roulis M, Rice T, Sivanathan KN, Zhou T, Solis AG, Honcharova-Biletska H, Vélez K, Hartner S, LowJS, Qu R, R. de Zoete MR,. Palm NW, Ring AM, Weber A, Moor AE, Kluger Y, Nowarski R# and Flavell RA#.​ *Co First Author and #Co Corresponding Author.

Effector TH17 Cells Give Rise to Long-Lived TRM Cells that Are Essential for an Immediate Response against Bacterial Infection. Cell. 2019, 178(5):1176-1188. Amezcua Vesely MC, Pallis P, Bielecki P, Low JS, Zhao J, Harman CCD, Kroehling L, Jackson R, Bailis W, Licona-Limón P, Xu H, Iijima N, Pillai PS, Kaplan DH, Weaver CT, Kluger Y, Kowalczyk MS, Iwasaki A, Pereira JP, Esplugues E, Gagliani N, Flavell RA.

Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity. Nature. 2019, 573(7772):69-74. Solis AG, Bielecki P, Steach HR, Sharma L, Harman CCD, Yun S, de Zoete MR, Warnock JN, To SDF, York AG, Mack M, Schwartz MA, Dela Cruz SS, Palm NW, Jackson R#, Flavell RA#. #Co Corresponding Author.

Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function. Nature. 2019, 571:403-407. Bailis W, Shyer JA, Zhao J, Canaveras JCG, Al Khazal FJ, Qu R, Steach HR, Bielecki P, Khan O, Jackson R, Kluger Y, Maher LJ, Rabinowitz J, Craft J, Flavell RA.

The Translation of Non-Canonical Open Reading Frames Controls Mucosal Immunity. Nature. 2018, 564:434-438. Jackson R, Kroehling L, Khitun A, Bailis W, Jarret A, York AG, Khan OM, Brewer JR, Skadow MH, Duizer C, Harman CCD, Chang L, Bielecki P, Solis AG, Steach HR, Slavoff S, Flavell RA.

The E3 ubiquitin ligase Pellino2 mediates priming of the NLRP3 inflammasome. Nature Communications. 2018, 9(1):1560.

Humphries F, Bergin R, Jackson R, Delagic N, Wang B, Yang S, Dubois AV, Ingram RJ, Moynagh PN.

Nlrp6 regulates intestinal antiviral innate immunity. Science. 2015, 350(6262):826–830. Wang P, Zhu S, Yang L, Cui S, Pan W, Jackson R, Zheng Y, Rongvaux A, Sun Q, Yang G, Gao S, Lin R, You F, Flavell R, Fikri, E.

Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis Cell. 2015, 163(6):1444-56. Nowarski R*, Jackson R*, Gagliani N, de Zoete M, Palm NW, Bailis W, Low J.S, Harman CD, Graham M, Elinav E, Flavell RA. *Co First Author.

Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell. 2014, 159(7):1563-77. Rongvaux, A, Jackson R, Harman CC, Li T, West AP, de Zoete MR, Wu Y, Yordy B, Lakhani SA, Kuan CY, Taniguchi T, Shadel GS, Chen ZJ Iwasaki A, Flavell RA.

Pellino3 ubiquitinates RIP2 and mediates NOD2-induced signaling and protective effects in colitis. Nature Immunology. 2013, 14(9):927-36. Yang S, Wang B, Humphries F, Jackson R, Healy M, Bergin R, Aviello G, Hall B, McNamara D, Darby T, Quinlan A, Shanahan F, Melger S, Fallon FG, Moynagh PN.

Regulation of Foxp3+ inducible Treg stability by the Suppressor of Cytokine Signaling -2 (SOCS2). Journal of Immunology. 2013, 190:3235-45. Knosp CA, Schiering C, Spence S, Carroll HP, Nel HJ, Osbourn M, Jackson R, Lyubomska O, MalissenB, Ingram R, Fitzgerald DC, Powrie F, Fallon PG, Johnston JA, Kissenpfennig A.

Changes in human dendritic cell number and function in severe obesity may contribute to increased susceptibility to viral infection. International Journal of Obesity. 2013, 26:2. O’Sea D, Corrigan M, Dunne MR, Jackson R, Woods C, Gaoatswe G, Moynagh PN, O’Connell J, Hogan AE.

Pellino3 targets the IRF7 pathway and facilitates autoregulation of TLR3- and viral-induced expression of type I interferons. Nature Immunology. 2012, 13:1055-1062. Siednienko J*, Jackson R*, Mellett M*, Delagic N, Yang S, Wang B, Tang LS, Callanan JJ, Mahon BP, Moynagh PN. *Co First Author.

SOCS2 regulates T helper type 2 differentiation and the generation of type 2 allergic responses. Journal of Experimental Medicine. 2011, 208:1523-31. Knosp CA, Carroll HP, Elliott J, Saunders SP, Nel HJ, Amu S, Pratt JC, Spence S, Doran E, Cooke N, Jackson R, Swift J, Fitzgerald DC, Heaney LG, Fallon PG, Kissenpfennig A, Johnston JA.

Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis. Diabetologia. 2011, 54:2745-2754. Hogan AE, Tobin AM, Ahern T, Corrigan MA, Gaoatswe G, Jackson R, O'Reilly V, Lynch L, Doherty DG, Moynagh PN, Kirby B, O'Connell J, O'Shea D.

Mal mediates TLR-induced activation of CREB and expression of IL-10. Journal of Immunology. 2011, 186: 4925-4935. Mellett M, Atzei P, Jackson R, O'Neill LA, Moynagh PN. Mal mediates TLR-induced activation of CREB and expression of IL-10.

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