Limited Contribution of IL-36 versus IL-1 and TNF Pathways in Host Response to Mycobacterial Infection

Segueni, Noria; Vigne, Solenne; Palmer, Gaby; Bourigault, Marie-Laure; Olleros, Maria L.; Vesin, Dominique; García, Irene; Ryffel, Bernhard; Quesniaux, Valérie; Gabay, Cem

doi:10.1371/journal.pone.0126058

Cited by 33 publications

(35 citation statements)

References 43 publications

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“…Indeed, IL‐36R‐deficient mice infected with M. bovis BCG did not exhibit any differences regarding survival as compared to wildtype mice even after several months of observation. Furthermore, in contrast to IL‐1R1‐deficient and particularly TNF‐α‐deficient mice, IL‐36R‐deficient mice did not show increased susceptibility to M. tuberculosis ‐induced lethality as compared to wildtype mice …”

Section: Immune Effects Of Il‐36mentioning

confidence: 85%

“…In contrast, IL‐36R‐deficient mice exhibited virtually similar findings as wildtype mice, indicating that IL‐36R does not contribute to papain‐induced lung inflammation . Intratracheal administration of LPS resulted in increased IL‐36γ expression in the lung . However, IL‐36R‐deficient mice display similar level of inflammatory responses as WT mice, indicating that IL‐36γ is not contributory to LPS‐induced lung inflammation (E. Woldt and C. Gabay, personal communication).…”

Section: Il‐36 In Lungmentioning

confidence: 99%

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Regulation and function of interleukin‐36 cytokines

Bassoy

Towne

Gabay

2017

Immunological Reviews

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161

177

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The interleukin (IL)-36 cytokines include 3 agonists, IL-36α, IL-36β, and IL-36γ that bind to a common receptor composed of IL-36R and IL-1RAcP to stimulate inflammatory responses. IL-36Ra is a natural antagonist that binds to IL-36R, but does not recruit the co-receptor IL-1RAcP and does not stimulate any intracellular responses. The IL-36 cytokines are expressed predominantly by epithelial cells and act on a number of cells including immune cells, epithelial cells, and fibroblasts. Processing of the N-terminus is required for full agonist or antagonist activity for all IL-36 members. The role of IL-36 has been extensively demonstrated in the skin where it can act on keratinocytes and immune cells to induce a robust inflammatory response that has been implicated in psoriatic disorders. Emerging data also suggest a role for this cytokine family in pulmonary and intestinal physiology and pathology.

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Section: Immune Effects Of Il‐36mentioning

confidence: 85%

Section: Il‐36 In Lungmentioning

confidence: 99%

Regulation and function of interleukin‐36 cytokines

Bassoy

Towne

Gabay

2017

Immunological Reviews

Self Cite

161

177

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“…Several lines of evidence, primarily from cell culture studies, suggest an important role in immunity. Although, for example, IFN-g abundance has been shown to be affected when IL-36 signaling is prevented during in vitro infections with fungi and mycobacteria (87,88,103), an effect of this upon infection outcomes in vivo has not been detected (107). Given the overlapping signaling mechanisms among IL-1 family members ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, it appears that the IL-36s can promote both the activation and expansion of T H 1-and cytotoxic cell-mediated immune responses, including production of the antimicrobial IFN-g. Whereas cells isolated from IL-1RL2 knockout mice produced less IFN-g than did cells from wild-type mice when infected with the vaccine strain Mycobacterium bovis Bacillus Calmette-Guérin (BCG) ex vivo (103), the IL-1RL2-deficient mice cleared BCG and pathogenic Mycobacterium tuberculosis as well as did wild-type mice (107). Thus, an essential role for endogenous IL-36 in immunity against microbes mediated by T H 1 or cytotoxic cells, or both, remains to be demonstrated in vivo.…”

Section: Function In Leukocyte Activationmentioning

confidence: 99%

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling

Jensen

2017

Sci. Signal.

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Pathogens deploy immune evasion strategies to successfully establish infections within their hosts. Naturally, the host responds by acquiring mechanisms to counter these strategies. There is increasing evidence that the three interleukin-36 (IL-36) cytokines, IL-36a, IL-36b and IL-36g, play important roles in host immunity. With a focus on the skin as a target for microbial and viral invasion, the current knowledge of IL-36 functions is reviewed. Furthermore, the hypothesis that the IL-36s have evolved to counteract virulence factors is presented using viruses as an example. The IL-36s are related to IL-1a, IL-1b, IL-18, and IL-33. Numerous viruses affecting the skin have developed immune evasion strategies that neutralize IL-1a, IL-1b, or IL-18 signaling or combinations of these pathways. Through small differences in activation mechanisms and receptor utilization, it is possible that IL-36 signaling may proceed unhindered in the presence of these viral inhibitors. Thus, one physiological function of the IL-36s may be to counteract microbial immune evasion.

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“…Histological analyses of infected organs were done at 4 weeks postinfection on fixed tissues for hematoxylin and eosin (H&E) and Ziehl-Neelsen (ZN) staining and on frozen livers for determination of acid phosphatase activity (24). Histopathological analyses were performed on tissue sections from lung and liver using digital microscopic images acquired by a Mirax digital slide scanner and analyzed with Pannoramic Viewer software (Carl Zeiss) (30). For liver analysis, the area with lesions was quantified and is presented as the percentage of the area with lesions, corresponding to the area of granulomas/surface area of the total liver, which was 50 Ϯ 11 mm 2 per liver section and animal.…”

Section: Methodsmentioning

confidence: 99%

Control of Mycobacterial Infections in Mice Expressing Human Tumor Necrosis Factor (TNF) but Not Mouse TNF

et al. 2015

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k Tumor necrosis factor (TNF) is an important cytokine for host defense against pathogens but is also associated with the development of human immunopathologies. TNF blockade effectively ameliorates many chronic inflammatory conditions but compromises host immunity to tuberculosis. The search for novel, more specific human TNF blockers requires the development of a reliable animal model. We used a novel mouse model with complete replacement of the mouse TNF gene by its human ortholog (human TNF [huTNF] knock-in [KI] mice) to determine resistance to Mycobacterium bovis BCG and M. tuberculosis infections and to investigate whether TNF inhibitors in clinical use reduce host immunity. Our results show that macrophages from huTNF KI mice responded to BCG and lipopolysaccharide similarly to wild-type macrophages by NF-B activation and cytokine production. While TNF-deficient mice rapidly succumbed to mycobacterial infection, huTNF KI mice survived, controlling the bacterial burden and activating bactericidal mechanisms. Administration of TNF-neutralizing biologics disrupted the control of mycobacterial infection in huTNF KI mice, leading to an increased bacterial burden and hyperinflammation. Thus, our findings demonstrate that human TNF can functionally replace murine TNF in vivo, providing mycobacterial resistance that could be compromised by TNF neutralization. This new animal model will be helpful for the testing of specific biologics neutralizing human TNF.T umor necrosis factor (TNF) is critical for resistance against intracellular bacterial infections; however, its dysregulation may be associated with the development of human immunopathologies (1-5). Anti-TNF therapies have shown their efficacy for the treatment of autoimmune inflammatory diseases, such as rheumatoid arthritis and Crohn's disease, and are being explored for the treatment of other severe human pathologies, such as chronic obstructive pulmonary disease (6-8). However, the complete blockade of TNF has confirmed the essential role of TNF in the control of tuberculosis (TB) infection, as treated patients develop both TB and nontuberculous mycobacterial diseases (9-12). TB is still a major health problem newly affecting in its active form nearly 9 million people every year. One-third of the global population is considered to be infected by Mycobacterium tuberculosis in a latent form (13). M. bovis BCG is used for vaccination in countries with a high TB incidence and appears to control severe forms of tuberculosis in children but fails to prevent TB in adults (14).TNF is initially synthesized as a membrane protein released under activation by infectious and inflammatory stimuli. Two types of TNF inhibitors blocking membrane and soluble TNF are currently used to treat inflammatory diseases and comprise anti-TNF antibodies (infliximab, adalimumab, certolizumab, etc.) and soluble TNF receptor 2 (sTNFR2; etanercept) (15). These drugs have distinct neutralization efficacies in human diseases, and they are associated with distinct risks of TB reactivation,...

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Limited Contribution of IL-36 versus IL-1 and TNF Pathways in Host Response to Mycobacterial Infection

Cited by 33 publications

References 43 publications

Regulation and function of interleukin‐36 cytokines

Regulation and function of interleukin‐36 cytokines

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling

Control of Mycobacterial Infections in Mice Expressing Human Tumor Necrosis Factor (TNF) but Not Mouse TNF

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