IL-36γ regulates mediators of tissue homeostasis in epithelial cells

Heath, Jacqueline E.; Scholz, Glen M.; Veith, Paul D.; Reynolds, Eric C.

doi:10.1016/j.cyto.2019.02.012

Cited by 13 publications

(11 citation statements)

References 55 publications

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“…IL-36 cytokines may be important in mucosal inflammation and homeostasis, possibly through modulation of γδ + T-cell immune functions (Ciccia et al 2015). TLR2 activation of human oral epithelial cells by P. gingivalis promoted the expression of IL-36γ and triggered chemotaxis of DCs and macrophages, amplifying the secretion of inflammatory cytokines, including IL-17 (Heath et al 2019), but also the antimicrobial peptide PGLYRP2, regulating oral mucosal homeostasis (Scholz et al 2018). Moreover, Candida albicans infection of the oral mucosa in mice induced a production of IL-36 as an innate protective response to this fungus (Verma et al 2018).…”

Section: Il-36mentioning

confidence: 99%

IL-1 Superfamily Members and Periodontal Diseases

et al. 2020

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Periodontitis is a complex, multifactorial chronic disease involving continuous interactions among bacteria, host immune/inflammatory responses, and modifying genetic and environmental factors. More than any other cytokine family, the interleukin (IL)–1 family includes key signaling molecules that trigger and perpetuate periodontal inflammation. Over the years, the IL-1 family expanded to include 11 members of cytokines, some with agonist activity (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, and IL-36γ), receptor antagonists (IL-1Ra, IL-36Ra), and 2 anti-inflammatory cytokines (IL-37, IL-38). The IL-1 receptor antagonist (IL-1Ra) has emerged as a pivotal player in the defense against periodontitis. IL-33 primarily induces the production of Th2-associated cytokines but acts as an “alarmin” via stimulation of mast cells. The IL-36 subclass of cytokines may be important in regulating mucosal inflammation and homeostasis. IL-37 suppresses innate and acquired immune responses. IL-38 is the most recent member of the IL-1 superfamily and has anti-inflammatory properties similar to those of IL-37 but through different receptors. However, limited evidence exists regarding the role of IL-37 and IL-38 in periodontitis. Despite the development of IL-1 blocking agents, therapeutic blockade of select IL-1 family members for periodontitis has only been partially investigated in preclinical and clinical research, while the development of IL-37 and IL-38 as novel anti-inflammatory drugs has not been considered adequately. Here, we review the key properties of the IL-1 family members and provide insights into targeting or promoting select cytokines as new therapeutic agents.

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Section: Il-36mentioning

confidence: 99%

IL-1 Superfamily Members and Periodontal Diseases

et al. 2020

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“…Importantly, IL-36R-deficient mice could be rescued from uncontrolled C. rodentium infection by administration of IL-23 during the early phase or IL-6 during the late phase of infection. Consistent with the DSS model of colitis, IL-36R signaling afforded critical host protective effects against C. rodentium associated with the induction of IL-22 and AMPs, although other barrier protective factors such as matrix metalloproteinase 9 and neutrophil gelatinase-associated lipocalin cannot be excluded (27). Thus, the inflammatory role of IL-36R signaling is instrumental in providing barrier protection from acute intestinal damage as well as enteric bacterial infection.…”

Section: Discussionmentioning

confidence: 84%

IL-36R signaling integrates innate and adaptive immune-mediated protection against enteropathogenic bacteria

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Abo

Kuczma

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Enteropathogenic bacterial infections are a global health issue associated with high mortality, particularly in developing countries. Efficient host protection against enteropathogenic bacterial infection is characterized by coordinated responses between immune and nonimmune cells. In response to infection in mice, innate immune cells are activated to produce interleukin (IL)-23 and IL-22, which promote antimicrobial peptide (AMP) production and bacterial clearance. IL-36 cytokines are proinflammatory IL-1 superfamily members, yet their role in enteropathogenic bacterial infection remains poorly defined. Using the enteric mouse pathogen, C.rodentium, we demonstrate that signaling via IL-36 receptor (IL-36R) orchestrates a crucial innate-adaptive immune link to control bacterial infection. IL-36R-deficient mice (Il1rl2−/−) exhibited significant impairment in expression of IL-22 and AMPs, increased intestinal damage, and failed to contain C. rodentium compared to controls. These defects were associated with failure to induce IL-23 and IL-6, two key IL-22 inducers in the early and late phases of infection, respectively. Treatment of Il1rl2−/− mice with IL-23 during the early phase of C. rodentium infection rescued IL-22 production from group 3 innate lymphoid cells (ILCs), whereas IL-6 administration during the late phase rescued IL-22-mediated production from CD4+ T cell, and both treatments protected Il1rl2−/− mice from uncontained infection. Furthermore, IL-36R-mediated IL-22 production by CD4+ T cells was dependent upon NFκB-p65 and IL-6 expression in dendritic cells (DCs), as well as aryl hydrocarbon receptor (AhR) expression by CD4+ T cells. Collectively, these data demonstrate that the IL-36 signaling pathway integrates innate and adaptive immunity leading to host defense against enteropathogenic bacterial infection.

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“…The "slow" responders displayed absence of certain key proteins such as C/EBP-beta, C5a, ceruloplasmin and lipocalin 2, which are involved in the regulation of genes involved in inflammatory responses (Bassoy, Towne, & Gabay, 2018;Chinery, Brockman, Dransfield, & Coffey, 1997;Kinoshita, Akira, & Kishimoto, 1992;Pless et al, 2008;Roy et al, 2002). Further, high concentrations of IL-36 may amplify the expression of antimicrobial proteins by gingival epithelial cells, thereby prohibiting bacterial growth (Heath, Scholz, Veith, & Reynolds, 2019). The combination of increased proinflammatory cytokines and reduced acute phase response proteins could shift the homeostatic equilibrium to render the tissue towards a more resilient biofilm challenge over longer periods without pronounced inflammatory damage (Reddi & Belibasakis, 2012;Westerlund et al, 1996).…”

Section: Discussionmentioning

confidence: 99%