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Semaphorin 3E Regulates the Response of Macrophages to Lipopolysaccharide-Induced Systemic Inflammation

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Semaphorin 3E Regulates the Response of Macrophages to Lipopolysaccharide-Induced Systemic Inflammation Semaphorin 3E Regulates the Response of Macrophages to Lipopolysaccharide-Induced Systemic Inflammation This information is current as Ashfaque Mohammed, Ifeoma Okwor, Lianyu Shan, of September 28, 2021. Chukwunonso Onyilagha, Jude E. Uzonna and Abdelilah S. Gounni J Immunol published online 27 November 2019 http://www.jimmunol.org/content/early/2019/11/26/jimmun ol.1801514 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/11/26/jimmunol.180151 Material 4.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *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 © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published November 27, 2019, doi:10.4049/jimmunol.1801514 The Journal of Immunology Semaphorin 3E Regulates the Response of Macrophages to Lipopolysaccharide-Induced Systemic Inflammation Ashfaque Mohammed,1 Ifeoma Okwor,1 Lianyu Shan, Chukwunonso Onyilagha, Jude E. Uzonna, and Abdelilah S. Gounni Semaphorin 3E (Sema3E) is a secreted protein that was initially discovered as a neuronal guidance cue. Recent evidence showed that Sema3E plays an essential role in regulating the activities of various immune cells. However, the exact role of Sema3E in macrophage function, particularly during inflammation, is not fully understood. We studied the impact of Sema3E gene deletion on macrophage function during the LPS-induced acute inflammatory response. We found that Sema3E-deficient (Sema3e2/2) mice were better protected from LPS-induced acute inflammation as exemplified by their superior clinical score and effective temperature control compared with their wild-type littermates. This superior control of inflammatory response in Sema3e2/2 mice was associated with significantly lower phosphorylation of ERK1/2, AKT, STAT3, and NF-kB, and a concomitant reduction Downloaded from in inducible NO synthase expression and production of TNF and IL-6 compared with their Sema3e+/+ littermates. Sema3e2/2 mice also contained significantly higher numbers of activated macrophages compared with their Sema3e+/+ littermates at both baselines and after LPS challenge. In vivo–specific deletion of the Sema3E high-affinity receptor, plexinD1, on macrophages led to the improvement in clinical disease following exposure to a lethal dose of LPS. Collectively, our data show that Sema3E plays an essential role in dampening the early inflammatory response to LPS by regulating macrophage function, suggesting an essential role of this pathway in macrophage inflammatory response. The Journal of Immunology, 2020, 204: 000–000. http://www.jimmunol.org/ acrophages are critical innate immune cells that process such as Chlamydia pneumoniae, thus playing an essential role in and present Ags to cells of the adaptive immune systems immune evasion (7). In the murine model of sepsis, pentamethox- M (1). They are the primary source of inflammatory/anti- yflavanone was shown to have a protective effect by its ability to inflammatory mediators such as chemokines, cytokines, oxygen- polarize macrophages to mostly M1 phenotype, and the adoptive free radicals, and lipid mediators (2), which help in destroying the transfer of M1 macrophages increased survival and improved dis- invading pathogens (1). ease in septic mice (8). Studies looking at the impact of sepsis on Depending on the prevailing microenvironment, macrophages monocytes/macrophages suggest that there is a suppression of the by guest on September 28, 2021 can be classically (M1) or alternatively (M2) activated. The dif- innate immune system following repeated LPS stimulation in vitro ferentiation into M1 or M2 is a well-coordinated process involving and the development of an M2 phenotype characterized by reduced many transcriptional, posttranslational, and signal transduction proinflammatory cytokine production (9, 10). Furthermore, blood pathways (3). Although M1 macrophages produce proinflammatory monocytes from septic patients show reduced ability to produce cytokines, M2 macrophages produce anti-inflammatory cytokines proinflammatory cytokines such as TNF, IL-16, and IL-12 (11), (4, 5), and the imbalance in these two populations may lead to suggesting an M2 phenotype. various diseases (6). The impact of M1 and M2 macrophages have Sema3E is a secreted protein initially known as a regulator of been studied in different disease models. M2 macrophages are the axonal growth of neurons (12). However, it has been shown to preferred cell type for the proliferation of intracellular pathogens exert various physiological and pathological roles in immune re- sponse, including cell migration (13), proliferation (14), and cytokine release via the binding to its receptor, plexinD1 (15). Department of Immunology, Max Rady College of Medicine, Rady Faculty of Health + + Sciences, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada Sema3E modulates the migration of CD4 CD8 T cells in the 1 thymus via inhibition of CCL25-CCR9 chemokine signaling, A.M. and I.O. are cofirst authors. which is a critical inducer of thymocyte migration from the cortex ORCID: 0000-0003-1265-6560 (A.S.G.). into the medulla (16), and through dynamic control of b1 integrin Received for publication December 21, 2018. Accepted for publication October 28, 2019. adhesion (16). Sema3E deficiency is associated with a significant reduction in macrophage numbers and their production of proin- This work was supported by the Manitoba Research Chair (to A.S.G.). A.M. was supported by a Children’s Hospital Research Institute of Manitoba studentship. flammatory cytokines (15). Furthermore, M1 macrophages stim- I.O. was supported by the International American Association of Immunologists ulated with oxidized low-density lipoprotein (LDL), LPS, and Fellowship. under hypoxic conditions upregulated Sema3E expression (17), Address correspondence and reprint requests to Dr. Abdelilah S. Gounni, Department and Sema3E was shown to attract and convert monocytes into of Immunology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, 419 Apotex Centre, 750 McDermot Avenue, Winnipeg, MB proinflammatory macrophages via the induction of p53 in adipose R3E 0T5, Canada. E-mail address: [email protected] tissue (15). These observations suggest that Sema3E could impact The online version of this article contains supplemental material. macrophage function and phenotype in various disease conditions. Abbreviations used in this article: BMDM, bone marrow–derived macrophage; iNOS, However, the role of Sema3E–plexinD1 interaction in LPS-induced inducible NO synthase; M1, classically activated; M2, alternatively activated; WT, acute inflammatory conditions and sepsis is unknown. Therefore, in wild-type. this study, we evaluated how Sema3E–plexinD1 pathway modulates Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 macrophage function and phenotype during LPS-induced systemic www.jimmunol.org/cgi/doi/10.4049/jimmunol.1801514 2 Sema3E AND SYSTEMIC INFLAMMATION inflammatory response. Our data show that deficiency of Sema3E (Qiagen, Mississauga, ON, Canada). High-Capacity cDNA Reverse Tran- leads to downregulation of the phosphorylation of key molecules scription Kit (Applied Biosystems) was used to synthesize cDNA from RNA involved in LPS-signaling pathways in macrophages leading to a according to the manufacturer’s instruction. Expression of TNF, IL-6, and housekeeping genes was analyzed by real-time PCR. The primer sequences concomitant reduction in the production of proinflammatory cy- were as follows: TNF forward 59-ATGAGCACAGAAAGCATGATC-3, tokines by these cells. Sema3E deficiency also resulted in reduced reverse 59-TACAGGCTTGTCACTCGAAT-39;IL-6forward59- phagocytosis and Ag-processing ability of peritoneal and bone GAGGATACCACTCCCAACAGA. marrow–derived macrophages (BMDMs), as well as in a higher CC-39, reverse 59-AAGTGCATCATCGTTGTTCATACA-39;GAPDH forward 59-AACTTTGGCATTGTGGAAGG-39, reverse 59-ACACATT- number of M2 macrophages. Specific deletion of the Sema3E GGGGGTAGGAACA-39. high-affinity receptor, plexinD1, on macrophages led to an im- The PCR reaction was run using BioRad CFX with protocol, initial one provement in clinical disease following exposure to a lethal dose cycle denaturation step: 10 min at 95˚C, 40 cycles of PCR (95˚C for 15 s, of LPS. Overall, our data show a previously undescribed role for 60˚C for 35 s and 72˚C for 35 s), one cycle of melting, and one cooling Sema3E/plexinD1 pathway in macrophage functions and re- cycle. Real-time RT-PCR data were quantified as Cq values that were inversely related to the amount of starting template. Results were nor- sponses to LPS and its role in the pathogenesis of LPS-induced malized to an internal control reference gene, as described previously (23). acute inflammatory response and sepsis. Flow
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