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Macrophage Inflammatory State Influences Susceptibility to Lysosomal Damage

Amanda O. Wong, View ORCID ProfileMatangi Marthi, Irene A. Owusu, Christiane E. Wobus, Joel A. Swanson
doi: https://doi.org/10.1101/2020.05.29.122390
Amanda O. Wong
*Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620
†Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620
‡Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI 48109-5620
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Matangi Marthi
*Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620
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  • ORCID record for Matangi Marthi
Irene A. Owusu
*Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620
§West African Center for Cell Biology of Infectious Pathogens, University of Ghana, Legon, Ghana
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Christiane E. Wobus
*Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620
†Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620
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Joel A. Swanson
*Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620
†Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620
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  • For correspondence: jswan@umich.edu
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Abstract

Macrophages possess mechanisms for reinforcing the integrity of their endolysosomal membranes against damage. This property, termed inducible renitence, was previously reported for macrophages stimulated with LPS, peptidoglycan, IFN-γ, or TNF-α. Here, we expanded the macrophage subtypes examined to include populations with well-defined functional roles in vivo: classically activated macrophages (CA-Mφ), alternatively activated macrophages (AA-Mφ), and regulatory macrophages (Reg-Mφ). We determined that renitence is a property of CA-Mφ and Reg-Mφ, but not of AA-Mφ. Furthermore, LPS-activated macrophages possess features of both CA-Mφ and Reg-Mφ, based on their cytokine secretion profiles. As the generation of these three classes of renitent macrophages required exposure to LPS, a Toll-like receptor (TLR) ligand, we assessed whether TLR stimulation generally induced renitence. Stimulation of TLRs 2/1, 3, and 4 induced renitence, whereas stimulation of TLRs 7/8 and 9 induced modest levels of lysosomal damage protection. Renitence induced by TLR stimulation required the signaling adaptors MyD88 and TRIF. Surprisingly, the specific signaling adaptor usage requirements for some TLRs differed from those established for canonical TLR signaling. Of note, renitence induced by LPS, a TLR4 ligand, required signaling through TRIF but not MyD88. Consistent with this pattern, the type I IFN response, which is triggered by LPS stimulation through a TRIF-dependent, MyD88-independent pathway, contributed to renitence. A biologically relevant type I IFN trigger in macrophages, murine norovirus-1 (MNV-1) infection, also induced renitence. This work establishes the concept that susceptibility to lysosomal damage within macrophages varies according to inflammatory state and depends on the type I IFN response.

Summary sentence Macrophages of distinct polarization states exhibit varying degrees of susceptibility to lysosomal damage reflecting their functional roles in host defense and immune regulation

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Abbreviations

    A2bR, adenosine 2b receptor; AA-Mφ, alternatively activated macrophages; Ado, adenosine; ANOVA, analysis of variance; ATP, adenosine triphosphate; AW, acid-washed; BMM, bone marrow-derived macrophages; CA-Mφ, classically activated macrophages; dsRNA, doublestranded RNA; ELISA, enzyme-linked immunosorbent assay; FBS, fetal bovine serum; Fdx, fluorescein dextran; FLA-ST, flagellin from Salmonella typhimurium; Gapdh, glyceraldehyde 3-phosphate dehydrogenase; IFITM3, interferon-induced transmembrane protein 3; IFN, interferon; IFN-γ, interferon-γ; Ifnar1, interferon-α/β receptor 1; IL-4, interleukin-4; IL-10, interleukin-10; IL-13, interleukin-13; L. monocytogenes, Listeria monocytogenes; ISG, interferon-stimulated gene; LPS, lipopolysaccharide; M-CSF, macrophage colony-stimulating factor; MDA5, melanoma differentiation-associated protein 5; MNV-1, murine norovirus-1; MOI, multiplicity of infection; MyD88, myeloid differentiation primary response 88; NCOA, nuclear receptor coactivator 7; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Pam3CSK4, Pam3CysSerLys4; PGE2, prostaglandin E2; poly(I:C), polyinosinic:polycytidylic acid; qPCR, quantitative polymerase chain reaction; R848, Resiquimod; Reg-Mφ, regulatory macrophages; RelA, nuclear factor NF-kappa-B p65 subunit; Relm-α, resistin-like molecule-α; RIG-I, retinoic acid-inducible gene I; ssRNA, single-stranded RNA; TLR, Toll-like receptor; TNF-α, tumor necrosis factor-α; TRIF, TIR (Toll-interleukin-1 receptor) domain-containing adaptor-inducing interferon-β; WT, wild-type.

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Posted May 31, 2020.
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Macrophage Inflammatory State Influences Susceptibility to Lysosomal Damage
Amanda O. Wong, Matangi Marthi, Irene A. Owusu, Christiane E. Wobus, Joel A. Swanson
bioRxiv 2020.05.29.122390; doi: https://doi.org/10.1101/2020.05.29.122390
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Macrophage Inflammatory State Influences Susceptibility to Lysosomal Damage
Amanda O. Wong, Matangi Marthi, Irene A. Owusu, Christiane E. Wobus, Joel A. Swanson
bioRxiv 2020.05.29.122390; doi: https://doi.org/10.1101/2020.05.29.122390

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