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TOLLIP Promotes Durable Alveolar Macrophage-Mediated Immunity During Mycobacterium Tuberculosis Infection by Resolving Cellular

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TOLLIP Promotes Durable Alveolar Macrophage-Mediated Immunity During Mycobacterium Tuberculosis Infection by Resolving Cellular bioRxiv preprint doi: https://doi.org/10.1101/2020.08.24.263624; this version posted August 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 TOLLIP promotes durable alveolar macrophage-mediated immunity during Mycobacterium 2 tuberculosis infection by resolving cellular stress from lipids. 3 4 Sambasivan Venkatasubramanian1, Courtney Plumlee2, Kim Dill-McFarland1, Gemma L. 5 Pearson3, Sara B. Cohen2, Anne Lietzke3, Amanda Pacheco3, Robyn Pryor1, Scott A. 6 Soleimanpour3,4, Matthew Altman1, Kevin B. Urdahl2,5, Javeed A. Shah1,6*. 7 1 Department of Medicine, University of Washington, Seattle, WA. 8 2 Seattle Children’s Research Institute, Seattle, WA. 9 3 Department of Internal Medicine, University of Michigan, Ann Arbor, MI. 10 4 VA Ann Arbor Healthcare System, Ann Arbor, MI. 11 5 Departments of Pediatrics and Immunology, University of Washington, Seattle, WA. 12 6 VA Puget Sound Healthcare System, Seattle, WA. * Correspondence: [email protected]; @ShahLab. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.24.263624; this version posted August 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 13 Summary 14 TOLLIP, a ubiquitin binding protein that controls multiple macrophage functions via 15 endoplasmic reticulum transport and autophagy, is associated with human tuberculosis (TB) 16 susceptibility and immune responses in genetic studies. We investigated how TOLLIP influences 17 immunity during Mycobacterium tuberculosis (Mtb) infection in the mouse model. During early 18 infection, Tollip-/- mice had reduced mycobacterial burden and increased innate immune 19 responses, but later, Tollip-/- mice developed worse disease and many foam cells within their 20 lung infiltrates. The delayed immune impairment was intrinsic to alveolar macrophages, 21 associated with cellular stress, and accompanied by lipid accumulation. Further, this phenotype 22 was reproducible with administration of exogenous lipids. Thus, TOLLIP expression in alveolar 23 macrophages is necessary for durable protection from prolonged Mtb infection by resolving 24 lipid-induced cellular stress. These descriptions define a critical role for TOLLIP as part of the 25 lipid-induced ER stress response, which is responsible for Mtb progression during post-primary 26 infection. 27 28 29 Keywords: TOLLIP, tuberculosis, macrophages, foam cells, innate immunity, unfolded protein 30 response, cellular homeostasis, lipid metabolism, autophagy, ER stress 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.24.263624; this version posted August 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 31 Introduction 32 Toll-Interacting Protein (TOLLIP) is a selective autophagy receptor and endosomal 33 sorting protein that was initially identified as a TLR and IL-1R binding protein (Burns et al., 34 2000) that also chaperones protein aggregates to the autophagosome via ER transport (Jongsma 35 et al., 2016; Lu et al., 2014). TOLLIP’s immune regulatory and homeostatic functions act in 36 competition, as excess protein aggregates prevent TOLLIP from influencing innate immune 37 responses (Pokatayev et al., 2020). In prior studies, we found that a functionally active single 38 nucleotide polymorphism upstream of the TOLLIP transcriptional start site that results in 39 diminished TOLLIP gene expression in monocytes is associated with increased risk for 40 pulmonary and meningeal TB, increased innate immune responses after Mtb infection, and 41 diminished BCG-specific T cell responses in South African infants (Shah et al., 2016; Shah et 42 al., 2017). Thus, the mechanism by which TOLLIP influences Mtb susceptibility remains poorly 43 defined, especially during chronic phases of infection. We evaluated how TOLLIP influences 44 pulmonary immune responses to Mtb infection and TB severity over time using Tollip-/- mice. 45 The impact of autophagy on Mtb pathogenesis is dramatic but incompletely understood. 46 After IFNγ activation, autophagy contributes to host defense within murine macrophages by 47 trafficking Mtb to autophagolysosomes for destruction, but this only represents a partial 48 contribution to Mtb clearance (Gutierrez et al., 2004; Ouimet et al., 2016). Autophagy also 49 dampens innate immune responses, including inflammasome and TLR activity (Matsuzawa- 50 Ishimoto et al., 2018), and the autophagy regulator Atg5 controls neutrophil-induced tissue 51 destruction and immunopathology after Mtb infection (Kimmey et al., 2015; Levine et al., 2011). 52 Autophagy is also induced to clear misfolded proteins and excess lipid, which is a component of 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.24.263624; this version posted August 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 53 the ER stress response and an important mechanism for maintaining cellular function over time 54 (Grootjans et al., 2016). ER stress induces multiple adverse effects in immune cells, but its 55 effects on Mtb-infected macrophages are not completely understood. 56 Unrelieved ER stress induces multiple adverse effects in macrophages that may influence 57 Mtb immune responses and pathogenesis. Stressed macrophages develop inflammatory 58 overreaction to bacterial products and TNF, which can worsen outcomes from TB infection 59 (Kaser et al., 2008; Roca et al., 2019). ER stress also diminishes protein translation, induces cell 60 cycle arrest, and impairs glycolysis, which are each important for Mtb control (Mizushima and 61 Komatsu, 2011; Russell et al., 2019). Last, ER stress strongly influences macrophage 62 polarization and differentiation, which may influence Mtb outcomes (Oh et al., 2012). In this 63 study, we found that TOLLIP participates in lipid clearance from alveolar macrophages (AM) 64 and is an important component of the ER stress response during prolonged Mtb infection in this 65 macrophage subtype. These data support targeting of TOLLIP as a strategy to overcome Mtb- 66 induced lipid accumulation and stress and as a way to maintain macrophage homeostasis during 67 chronic Mtb disease. 68 Results 69 Tollip-/- macrophages develop proinflammatory cytokine bias after Mtb infection. In preliminary 70 experiments, we identified a functional single nucleotide polymorphism in the TOLLIP promoter 71 region that was associated with decreased TOLLIP mRNA expression in peripheral blood 72 monocytes and hyperinflammatory cytokine responses after TLR stimulation and Mtb infection 73 (Shah et al., 2016; Shah et al., 2017; Shah et al., 2012). This variant was also associated with 74 increased risk for pulmonary and meningeal TB in genetic studies (Shah et al., 2012). To link 4 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.24.263624; this version posted August 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 75 these human genetic observations with our small animal model, we evaluated the functional 76 capacity of Tollip-/- macrophages to produce pro- and anti-inflammatory cytokines after TLR 77 stimulation and Mtb infection. We isolated peritoneal macrophages (PEM), plated them ex vivo 78 and stimulated them with LPS (TLR4 ligand; 10ng/ml), PAM3 (TLR2/1 ligand; 250ng/ml), or 79 Mtb whole cell lysate (1µg/ml). Tollip-/- PEM secreted more TNF than control after all 80 stimulation conditions (Figure 1A, LPS p = 0.01, PAM3 p = 0.002, Mtb lysate p = 0.01, n = 9). 81 Conversely, Tollip-/- PEM induced less IL-10 than controls (Figure 1B, LPS p = 0.01, PAM3 p = 82 0.02, Mtb lysate p =0.03, n = 9). We infected PEM with live Mtb H37Rv strain (MOI 2.5) 83 overnight and measured TNF, IL-1β and IL-10. After infection, Tollip-/- PEM secreted more 84 TNF and IL-1β, while inducing less IL-10 than controls (MOI 2.5) (Figure 1C-E; p=0.03, 85 p=0.03, and p=0.02 respectively), which is consistent with macrophage responses observed in 86 human cell lines and genetic variants associated with diminished TOLLIP mRNA transcript 87 (Shah et al., 2017; Shah et al., 2012). Thus, murine TOLLIP recapitulated the functional 88 phenotypes of human TOLLIP after Mtb infection in macrophages. 89 90 TOLLIP is required to control Mtb infection. Human studies suggest that TOLLIP variants are 91 associated with TB susceptibility (Shah et al., 2016; Shah et al., 2017; Shah et al., 2012). Further, 92 a functionally active variant in the TOLLIP promoter was associated with decreased TOLLIP 93 mRNA expression in monocytes and increased innate immune responses to Mtb infection, but 94 diminished BCG-specific T cells responses (Shah et al., 2017). Therefore, we evaluated how 95 TOLLIP influenced TB outcomes in the knockout mouse model to elucidate the mechanistic 96 underpinnings of TOLLIP in the immune response to Mtb in vivo. We infected Tollip-/- mice and 97 littermate controls expressing Tollip (WT) with 100 cfu of Mtb H37Rv strain via aerosol and 5 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.24.263624; this version posted August 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
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