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Mycobacterium Tuberculosis Lipoarabinomannan Activates Mycobacterium tuberculosis Lipoarabinomannan Activates Human Neutrophils via a TLR2/1 Mechanism Distinct from Pam 3CSK4 This information is current as of October 3, 2021. Jessica S. Hook, Mou Cao, Kayson Weng, Nedha Kinnare and Jessica G. Moreland J Immunol published online 23 December 2019 http://www.jimmunol.org/content/early/2019/12/21/jimmun ol.1900919 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/12/22/jimmunol.190091 Material 9.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 October 3, 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 December 23, 2019, doi:10.4049/jimmunol.1900919 The Journal of Immunology Mycobacterium tuberculosis Lipoarabinomannan Activates Human Neutrophils via a TLR2/1 Mechanism Distinct from Pam3CSK4 Jessica S. Hook,* Mou Cao,* Kayson Weng,* Nedha Kinnare,* and Jessica G. Moreland*,† Neutrophils, polymorphonuclear (PMN) leukocytes, play an important role in the early innate immune response to Mycobacterium tuberculosis infection in the lung. Interactions between PMN and mycobacterial lipids impact the activation state of these migrated cells with consequences for the surrounding tissue in terms of resolution versus ongoing inflammation. We hypothesized that lipoarabinomannan from M. tuberculosis (Mtb LAM) would prime human PMN in a TLR2-dependent manner and inves- tigated this with specific comparison with the purified synthetic TLR2 agonists, Pam3CSK4 and FSL-1. In contrast to Pam3CSK4 and FSL-1, we found Mtb LAM did not induce any of the classical PMN priming phenotypes, including enhancement of NADPH oxidase activity, shedding of L-selectin, or mobilization of CD11b. However, exposure of PMN to Mtb LAM did elicit pro- and anti- Downloaded from inflammatory cytokine production and release in a TLR2/1-dependent manner, using the TLR1 single-nucleotide polymorphism rs5743618 (1805G/T) as a marker for TLR2/1 specificity. Moreover, Mtb LAM did not elicit p38 MAPK phosphorylation or endocytosis, although these processes occurred with Pam3CSK4 stimulation, and were necessary for the early priming events to occur. Interestingly, Mtb LAM did not abrogate priming responses elicited by Pam3CSK4. Notably, subfractionation of light membranes from Pam3CSK4 versus Mtb LAM–stimulated cells demonstrated differential patterns of exocytosis. In summary, Mtb LAM activates PMN via TLR2/1, resulting in the production of cytokines but does not elicit early PMN priming responses, as http://www.jimmunol.org/ seen with Pam3CSK4. We speculate that the inability of Mtb LAM to prime PMN may be due to differential localization of TLR2/1 signaling. The Journal of Immunology, 2020, 204: 000–000. uberculosis (Tb) is an ongoing global health concern In more general terms, there is increasing understanding that causing an estimated 1.2 million deaths in 2018 (1). Al- PMN called to a site of infection and inflammation can cause T though the role of macrophages in the pathogenesis of significant host tissue damage by release of toxic contents including disease caused by Mycobacterium tuberculosis is very well char- proteases and reactive oxygen species (ROS) (4, 5). In contrast, acterized, there is more recent recognition of a critical role for certain signaling conditions lead to neutrophil-mediated suppres- by guest on October 3, 2021 neutrophils, polymorphonuclear (PMN) leukocytes, in the early sion of inflammation by release of anti-inflammatory cytokines (6) pulmonary inflammatory response (2). The role of PMN in the and the initiation of an apoptosis program which not only limits pathogenesis has been relatively understudied, but it has been neutrophil-mediated damage, but alters the macrophage inflam- demonstrated that PMN are recruited in large numbers to the lung matory potential as a consequence of efferocytosis (7, 8). Two tissue surrounding the forming granuloma (3). During the process major avenues for perpetuation of inflammatory damage by PMN of migration from the vascular space into the lung, PMN are likely are via activation of the NADPH oxidase 2 (NOX2) and through to encounter not only host chemokines and cytokines, but also azurophilic or primary granule exocytosis (9, 10). mycobacterial proteins and lipids. The impact of the PMN inter- The literature to date lacks clarity on how M. tuberculosis actions with these bacterial products determines the activation and some of its products impact PMN NOX2 activity. Lip- state of the migrated PMN with significant potential to further oarabinomannan (LAM) is a glycolipid in the mycobacterial cell amplify the ongoing inflammatory process. wall that plays an important role in the pathogenesis of Tb (11). The structure of LAM varies among mycobacterial strains and is known to impact mycobacterial virulence (11). LAM consists of a *Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, glycosylphosphatidyl anchor, a mannan core, and arabinan. The TX 75390; and †Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390 terminal arabinan may be modified, resulting in heterogeneity ORCIDs: 0000-0001-9614-6335 (K.W.); 0000-0003-1467-5722 (N.K.). among mycobacterial strains that contributes to diverse host im- mune responses and mycobacterial virulence. The addition of Received for publication August 1, 2019. Accepted for publication November 22, 2019. mannose caps results in mannosylated LAM and is common Address correspondence and reprint requests to Dr. Jessica G. Moreland, University among, but not exclusive to, pathogenic mycobacterial strains, of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX including the most commonly studied pathogenic M. tuberculosis 75390-8548. E-mail address: [email protected] strain, H37Rv (11). Little is known about the interaction of LAM The online version of this article contains supplemental material. with human PMN. In studies performed nearly two decades ago Abbreviations used in this article: DPBS, Dulbecco’s PBS; FFE, free-flow electro- using relatively insensitive measures of ROS production, incuba- phoresis; FSC-SSC, forward versus side scatter; LAM, lipoarabinomannan; LAP, latent alkaline phosphatase; LM, light membrane; Mtb LAM, LAM from M. tuberculosis; tion of PMN with purified LAM did not elicit any superoxide NET, neutrophil extracellular trap; NOX2, NADPH oxidase 2; PM, plasma membrane production directly (12), whereas incubation with certain strains vesicle; PMN, polymorphonuclear; ROS, reactive oxygen species; SNP, single- of whole live Mycobacteria elicited ROS production in a TLR2- nucleotide polymorphism; SV, secretory vesicle; Tb, tuberculosis. dependent manner (13). Although purified LAM did not Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 directly elicit a respiratory burst, it was demonstrated to induce www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900919 2 NEUTROPHIL TLR2/1 ACTIVATION BY Mtb LAM very-low-magnitude priming of fMLF-mediated ROS production (Danvers, MA). Streptavidin-HRP, IL-6, and IL-1Ra ELISA reagents were as measured by chemiluminescence (14). We have recently shown from R&D Systems (Minneapolis, MN). Fluorescently conjugated secondary that exocytosis of the azurophilic granule subset can be primed by Abs were from Jackson ImmunoResearch Laboratories (West Grove, PA). FSL-1 and Pam3CSK4 were from InvivoGen (San Diego, CA). Purified Mtb exposure to inflammatory cytokines, with enhanced release after LAM was obtained through Biodefense and Emerging Infections Research secondary stimulation (15), a process that might be highly relevant Resources Repository, National Institute of Allergy and Infectious Diseases, in Tb pathogenesis. National Institutes of Health: M. tuberculosis, strain H37Rv, purified LAM, Neutrophil priming, or preactivation, describes a state whereby NR-14848. p38 MAPK (SB203580), and control (SB202474) inhibitors were from Cayman Chemical (Ann Arbor, MI). Dyngo-4A was from Abcam. PMN encounter a primary stimulus and undergo phenotypic Additional reagents were obtained from Thermo Fisher Scientific changes that allow markedly enhanced responsiveness to a unique (Pittsburgh, PA). All buffers and reagents were strictly endotoxin free. subsequent stimulus. Our laboratory has studied neutrophil priming Human PMN purification in response to both bacterial and host products, most recently using synthetic TLR2 ligands as priming stimuli (16–19). In this most Human PMN were isolated according to standard techniques from heparin recent study, we discovered that the TLR1 single-nucleotide anticoagulated venous blood from healthy consenting adults following polymorphism (SNP) rs5743618 (1805G/T) significantly im- written informed consent
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