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Recovery from Lipopolysaccharide Tolerance Macrophage Identification of a Unique Hybrid Macrophage-Polarization State following Recovery from Lipopolysaccharide Tolerance This information is current as Christine O'Carroll, Ailís Fagan, Fergus Shanahan and of September 30, 2021. Ruaidhrí J. Carmody J Immunol 2014; 192:427-436; Prepublished online 11 December 2013; doi: 10.4049/jimmunol.1301722 http://www.jimmunol.org/content/192/1/427 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2013/12/27/jimmunol.130172 Material 2.DC1 http://www.jimmunol.org/ References This article cites 62 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/192/1/427.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 30, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Identification of a Unique Hybrid Macrophage-Polarization State following Recovery from Lipopolysaccharide Tolerance Christine O’Carroll,* Ailı´s Fagan,† Fergus Shanahan,* and Ruaidhrı´ J. Carmody‡ LPS tolerance is an essential immune-homeostatic response to repeated exposure to LPS that prevents excessive inflammatory responses. LPS tolerance induces a state of altered responsiveness in macrophages, resulting in repression of proinflammatory gene expression and increased expression of factors that mediate the resolution of inflammation. In this study, we analyzed the transcriptional plasticity of macrophages following LPS tolerance using genome-wide transcriptional profiling. We demonstrate that LPS tolerance is a transient state and that the expression of proinflammatory genes is restored to levels comparable to the acute response to LPS. However, following recovery from LPS tolerance a number of genes remained locked in a tolerizable state, including IL-33, CD86, IL-10, and NFIL3. Furthermore, we identified of a number of genes uniquely induced following recovery from LPS tolerance. Thus, macrophages adopt a unique transcriptional profile following recovery from LPS tolerance and have Downloaded from a distinct expression pattern of regulators of Ag presentation, antiviral responses, and transcription factors. Our data suggest that recovery from LPS tolerance leads to a hybrid macrophage activation state that is proinflammatory and microbicidal in nature but that possesses a regulatory anti-inflammatory profile distinct from that of LPS-tolerant and LPS-activated macrophages. The Journal of Immunology, 2014, 192: 427–436. nflammation is a powerful, organized, and complex immu- LPS tolerance may lead to profound consequences, including death as http://www.jimmunol.org/ nological response to infection and tissue damage. TLRs are the result of excessive and uncontrolled cytokine levels (4, 7). I key sensors of microbial presence and host damage and are Recent transcriptional profiling of macrophages identified two central to innate inflammatory responses (1). TLR4 is the most classes of LPS-responsive genes: those that are suppressed during extensively studied TLR that recognizes LPS, an outer membrane LPS tolerance, so-called “tolerizable genes,” which include TNF-a cell wall component of Gram-negative bacteria. Ligation of TLR4 and IL-6, and those genes whose expression is maintained or even triggers intracellular-signaling pathways, culminating in the pro- increased during LPS tolerance, so-called “nontolerizable genes,” duction of proinflammatory cytokines, chemokines, and type 1 IFNs which include antimicrobial and anti-inflammatory genes. Chro- to effectively clear infection (1–3). Chronic or repeated exposure of matin modifications are associated with LPS tolerance, which macrophage to LPS leads to a phenomenon termed LPS tolerance, promotes a global transcriptional switch in macrophage gene ex- by guest on September 30, 2021 which represents a state of altered responsiveness to additional LPS pression (8). This unique transcriptional signature was proposed to challenge. The most notable feature of LPS tolerance is the sharp drive a phenotypic switch in macrophage polarization from a reduction in proinflammatory cytokine expression, including TNF-a proinflammatory to an anti-inflammatory proresolution state (8). and IL-6, in response to LPS stimulation. LPS tolerance is critical in A number of negative regulators of TLR-induced responses have limiting the innate response to infection to reduce host damage been identified that are critical in promoting LPS tolerance. These and promote the resolution of inflammation (4–6). Failure to enforce include regulators of TLR4-induced signal transduction, such as IRAK-M, TOLLIP, SHIP, and A20, and transcriptional regulators, such as Bcl-3 (9–16). Macrophages display a spectrum of activation states, which are *Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; broadly described as classical (M1), alternative (M2), and regu- †Department of Surgery, Royal College of Surgeons Ireland, Dublin 2, Ireland; and ‡Centre for Immunobiology, Institute of Infection, Immunity, and Inflammation, latory (17, 18). M1 macrophages are proinflammatory cytotoxic College of Medicine, Veterinary, and Life Sciences, University of Glasgow, Glasgow phagocytes and promote Th1 adaptive-immune responses fol- G12 8TA, United Kingdom lowing TLR and IFN-g challenge (17, 18). In contrast, IL-4/IL-13 Received for publication July 1, 2013. Accepted for publication October 30, 2013. specifically polarizes macrophages to an alternatively activated This work was supported by Science Foundation Ireland Grant 08/IN.1/B1843, M2 state. These cells are anti-inflammatory, promote tissue remod- Centres for Science, Engineering and Technology Grant 07/CE/B1368, and the Marie Curie International Reintegration grant program. eling, and are important in mediating Th2 immunity to fungal and parasitic infections (17, 19, 20). Regulatory macrophages are Microarray profiling data have been deposited in the National Center for Biotech- nology Information Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/ immune regulatory cells that display both anti-inflammatory and geo/query/acc.cgi?acc=GSE47783) under series entry identifier GSE47783. proinflammatory features through suppression of some proin- Address correspondence and reprint requests to Dr. Ruaidhri J. Carmody, Centre for flammatory genes and increased production of IL-10, while main- Immunobiology, Institute of Infection, Immunity, and Inflammation, College of Med- taining Ag-presenting capacity. Immune complexes and FcR icine, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1QH, U.K. E-mail address: [email protected] engagement in conjunction with TLR activation polarize macro- The online version of this article contains supplemental material. phages toward a regulatory state. In addition, other stimuli, in- Abbreviations used in this article: A, acute response; BMDM, bone marrow–derived cluding glucocorticoids, PGs, and apoptotic cells, can polarize macrophage; COA, correspondence analysis; FMO, fluorescence minus one; GO, macrophages into a regulatory macrophage state (17). These three gene ontology; M1, classical; M2, alternative; N, naive; PC, principal component; activation states represent the main groups in the emerging spec- qRT-PCR, quantitative real-time PCR; RM, recovered macrophage; T, LPS tolerized. trum of macrophage polarization. However, because of the large Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 number of activation stimuli that macrophages encounter in vivo, www.jimmunol.org/cgi/doi/10.4049/jimmunol.1301722 428 TRANSCRIPTION AND RECOVERY FROM TOLERANCE many hybrid activation states exist. These include tumor-associated Thioglycollate-elicited peritoneal macrophages macrophages, intestinal macrophages, and LPS-tolerized (T) mac- Peritoneal macrophages were isolated as previously described (31). rophages, all of which share overlapping features of M1, M2, and Thioglycollate-elicited peritoneal macrophages were isolated from 6–8- regulatory macrophages while displaying distinct markers of acti- wk-old female C57BL/6 mice by peritoneal lavage 3 d post-i.p. injection vation (21–26). with 1 ml sterile 4% thioglycollate. Briefly, 10 ml ice-cold sterile PBS was LPS tolerance polarizes macrophages into an anti-inflammatory injected into the peritoneal cavity, followed by gentle massaging of the cavity to allow cells to be collected and withdrawn by peritoneal lavage. activation state distinct from M2 macrophage polarization (21– Collected cells from three mice were pooled, passed through a 70-mM cell 23). Although transcriptomics analysis has been performed on LPS strainer (BD Biosciences), and centrifuged at 4˚C for 5 min at 300 3 g. tolerance (8, 22, 27), the plasticity of this state has not been ex- Isolated thioglycolate-elicited peritoneal
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