• How one inflammatory disorder exacerbate

    From ScienceDaily@1:317/3 to All on Wednesday, April 27, 2022 22:30:50
    How one inflammatory disorder exacerbates another

    Date:
    April 27, 2022
    Source:
    University of Pennsylvania
    Summary:
    People with severe gum disease are at a higher risk of other
    inflammatory conditions, such as heart disease and arthritis,
    and the reverse is true as well. New research unpacks the
    mechanism underlying this association, demonstrating in mice that
    a susceptibility to arthritis can be transmitted by a bone marrow
    transplant if the donor has gum inflammation.



    FULL STORY ==========================================================================
    The immune system remembers. Often this memory, primed by past encounters
    with threats like bacteria or viruses, is an asset. But when that memory
    is sparked by internal drivers, like chronic inflammation, it can prove detrimental, perpetuating a misguided immune response.


    ==========================================================================
    In a new paper in Cell, researchers from the School of Dental Medicine, together with an international team including colleagues at the Technical University of Dresden, lay out the mechanism by which innate immune
    memory can cause one type of inflammatory condition -- in this example,
    gum disease -- to increase susceptibility to another -- here, arthritis
    -- through alterations to immune cell precursors in the bone marrow. In
    a mouse model, the team demonstrated that recipients of a bone marrow transplant were predisposed to more severe arthritis if their donor had inflammatory gum disease.

    "Although we use periodontitis and arthritis as our model, our findings go above and beyond these examples," says George Hajishengallis, a professor
    in Penn Dental Medicine and a corresponding author on the work. "This
    is in fact a central mechanism, a unifying principle underlying the
    association between a variety of comorbidities." The researchers note
    that this mechanism may also prompt a reconsideration of how bone marrow
    donors are selected, as donors with certain types of immune memory caused
    by underlying inflammatory conditions might put bone marrow transplant recipients at a higher risk of inflammatory disorders.

    Basis in the bone marrow In previous work, Hajishengallis had partnered
    with co-corresponding author Triantafyllos Chavakis of Technical
    University of Dresden and collaborators to explore the role of innate
    immune memory. Their findings showed that, just like the adaptive immune system's T cells and B cells, the innate immune system's myeloid cells,
    such as neutrophils and macrophages, could "remember" past encounters,
    becoming more responsive when exposed to a new threat. The work also
    pinpointed how this memory was encoded, tracing it to the bone marrow,
    and showed that this "trained immunity" could be transferred from
    one organism to another through a bone marrow transplant, protecting
    recipients from cancer through an innate immune response.



    ========================================================================== While that is good news, Hajishengallis and Chavakis also believed that
    trained immunity could be detrimental in the right contexts. While
    attending a meeting on innate immunity in Greece in 2019, the two
    scientists brainstormed over dinner at an outdoor tavern, jotting down
    their thoughts on a napkin. They later formalized some of their hypotheses about this potential "dark side" of trained immune in a publication in
    Nature Reviews Immunology in 2021.

    "The thoughts went like this: We knew the gum disease periodontitis
    increased the risk of comorbidities like cardiovascular disease,"
    says Hajishengallis.

    "And the reverse is also true: People with the inflammatory disease
    colitis, for example, have an increased prevalence of periodontal
    disease. Different mechanisms have been proposed, but no one unifying
    mechanism could explain this bidirectionality." "We started thinking
    about a possible unifying mechanism that could underlie the association
    between several distinct comorbidities," says Chavakis.

    Building on their earlier discovery related to "trained" precursors in
    the bone marrow, the scientists set out to see whether they could trace
    the source of the association between comorbidities to the innate immune training they already knew was happening in the bone marrow.

    Setting out to test this hypothesis, the team first showed that, within a
    week of inducing a mouse to have periodontal disease, the animal's myeloid cells and their progenitor cells expanded in the bone marrow. Examining
    these cells weeks later, after periodontitis was intentionally resolved,
    the researchers did not notice significant changes in how the cells
    looked or behaved.



    ========================================================================== However, these progenitor cells appeared to have memorized the
    inflammation they were exposed to, as they harbored important epigenetic changes: alterations in molecular markers that affect the ways genes
    are turned on and off but do not alter the actual DNA sequence. The
    researchers found that these alterations, triggered by inflammation, could alter the manner in which the genes would be expressed after a future challenge. The overall pattern of epigenetic changes, the researchers
    noted, was associated with known signatures of the inflammatory response.

    Mice with induced periodontal disease also had more severe responses to
    a later immune system challenge, evidence of trained immunity.

    To put the whole picture together regarding the link between inflammatory conditions, the "critical experiment," as Hajishengallis explains,
    was a bone marrow transplant. Mice that had periodontitis, a severe
    form of gum disease, served as donors, as did a group of healthy mice
    serving as controls. Two hundred stem cells from their bone marrow were transplanted into mice that had never had gum disease and which had had
    their own bone marrow irradiated. A few months later, these mice were
    exposed to collagen antibodies, which trigger arthritis.

    "Mice that received the transplant from mice with periodontitis developed
    more severe arthritis than mice that received a donation of stem cells
    from periodontally healthy mice," says Hajishengallis.

    "And higher joint inflammation in recipient mice was due to inflammatory
    cells deriving from the periodontitis-trained stem cells," says Chavakis.

    Further experiments suggested that the signaling pathway governed by
    a receptor for the molecule IL-1 played a vital role in contributing
    to this inflammatory memory. Mice that lacked IL-1 receptor signaling
    could not generate the immune memory that made the recipient mice more susceptible to comorbidities, the researchers found.

    The work has implications for bone marrow transplants in humans, a common course of therapy in addressing blood cancers.

    "Of course, it's a great thing if you find a matching donor for bone
    marrow transplantation," says Hajishengallis. "But our findings suggest
    that it's important for clinicians to keep in mind how the medical
    history of the donor is going to affect the health of the recipient."
    The work also underscores that blocking IL-1 receptor signaling could
    be an effective approach to mitigate against these knock-on effects of
    trained immunity.

    "We've seen anti-IL-1 antibodies used in clinical trials for
    atherosclerosis with excellent results," Hajishengallis says. "It could
    be that it was in part because it was blocking this maladaptive trained immunity." Follow-up projects are examining how other inflammatory
    conditions, may be linked with periodontal disease, a sign, the
    researchers say, of how crucial oral health is to overall health.

    "I'm proud for the field of dentistry that this work, with significance to
    a wide range of medical conditions, began by investigating oral health," Hajishengallis says.

    George Hajishengallis is the Thomas W. Evans Centennial Professor in
    the Department of Basic and Translational Sciences in the University of Pennsylvania School of Dental Medicine.

    In addition to Hajishengallis and Chavakis, coauthors on the study were
    Penn Dental Medicine's Xiaofei Li, Hui Wang, and Gundappa Saha; Xiang
    Yu of Penn's Department of Biology and Shanghai Jiao Tong University;
    Technical University of Dresden's Lydia Kalafati, Charalampos Ioannidis,
    and Ioannis Mitroulis; and Mihai G. Netea of Radboud University of
    Medical Center and the University of Bonn.

    The study was supported in part by the National Institutes of Health
    (grants DE029436 and DE031206) and the Deutsche Forschungsgemeinschaft.


    ========================================================================== Story Source: Materials provided by University_of_Pennsylvania. Note:
    Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Xiaofei Li, Hui Wang, Xiang Yu, Gundappa Saha, Lydia Kalafati,
    Charalampos Ioannidis, Ioannis Mitroulis, Mihai G. Netea,
    Triantafyllos Chavakis, George Hajishengallis. Maladaptive
    innate immune training of myelopoiesis links inflammatory
    comorbidities. Cell, 2022; DOI: 10.1016/ j.cell.2022.03.043 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/04/220427115816.htm

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