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Tissue-resident macrophages actively suppress IL-1beta release via a reactive prostanoid/IL-10 pathway.

ABSTRACT: The alarm cytokine interleukin-1? (IL-1?) is a potent activator of the inflammatory cascade following pathogen recognition. IL-1? production typically requires two signals: first, priming by recognition of pathogen-associated molecular patterns leads to the production of immature pro-IL-1?; subsequently, inflammasome activation by a secondary signal allows cleavage and maturation of IL-1? from its pro-form. However, despite the important role of IL-1? in controlling local and systemic inflammation, its overall regulation is still not fully understood. Here we demonstrate that peritoneal tissue-resident macrophages use an active inhibitory pathway, to suppress IL-1? processing, which can otherwise occur in the absence of a second signal. Programming by the transcription factor Gata6 controls the expression of prostacyclin synthase, which is required for prostacyclin production after lipopolysaccharide stimulation and optimal induction of IL-10. In the absence of secondary signal, IL-10 potently inhibits IL-1? processing, providing a previously unrecognized control of IL-1? in tissue-resident macrophages.

SUBMITTER: Ipseiz N

PROVIDER: S-EPMC7360975 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Tissue-resident macrophages actively suppress IL-1beta release via a reactive prostanoid/IL-10 pathway.

Ipseiz Natacha N Pickering Robert J RJ Rosas Marcela M Tyrrell Victoria J VJ Davies Luke C LC Orr Selinda J SJ Czubala Magdalena A MA Fathalla Dina D Robertson Avril Ab AA Bryant Clare E CE O'Donnell Valerie V Taylor Philip R PR

The EMBO journal 20200602 14

The alarm cytokine interleukin-1β (IL-1β) is a potent activator of the inflammatory cascade following pathogen recognition. IL-1β production typically requires two signals: first, priming by recognition of pathogen-associated molecular patterns leads to the production of immature pro-IL-1β; subsequently, inflammasome activation by a secondary signal allows cleavage and maturation of IL-1β from its pro-form. However, despite the important role of IL-1β in controlling local and systemic inflammati ...[more]

PMID: 32484988

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Project description:Coxiella burnetii is a highly infectious pathogen that causes Q fever, a leading cause of culture-negative endocarditis. Coxiella first targets alveolar macrophages and forms a phagolysosome-like compartment called the C oxiella - C ontaining V acuole (CCV). Successful host cell infection requires the Type 4B Secretion System (T4BSS), which translocates bacterial effector proteins across the CCV membrane into the host cytoplasm, where they manipulate numerous cell processes. Our prior transcriptional studies revealed that Coxiella T4BSS blocks IL-17 signaling in macrophages. Given that IL-17 is known to protect against pulmonary pathogens, we hypothesize that C. burnetii T4BSS downregulates intracellular IL-17 signaling to evade the host immune response and promote bacterial pathogenesis. Using a stable IL-17 promoter reporter cell line, we confirmed that Coxiella T4BSS blocks IL-17 transcription activation. Assessment of the phosphorylation state of NF-κB, MAPK, and JNK revealed that Coxiella downregulates IL-17 activation of these proteins. Using ACT1 knockdown and IL-17RA or TRAF6 knockout cells, we next determined that IL17RA-ACT1-TRAF6 pathway is essential for the IL-17 bactericidal effect in macrophages. In addition, macrophages stimulated with IL-17 generate higher levels of reactive oxygen species, which is likely connected to the bactericidal effect of IL-17. However, C. burnetii T4SS effector proteins block the IL-17-mediated oxidative stress, suggesting that Coxiella blocks IL-17 signaling to avoid direct killing by the macrophages.ImportanceBacterial pathogens are constantly evolving mechanisms to modulate the hostile host environment encountered during infection. Coxiella burnetii , the causative agent of Q fever, is a fascinating example of intracellular parasitism. Coxiella survives in a phagolysosome-like vacuole and uses the Dot/Icm type IVB secretion system (T4BSS) to deliver bacterial effector proteins into the host cell cytoplasm to manipulate several host cell functions. We recently demonstrated that Coxiella T4BSS blocks the IL-17 signaling in macrophages. Here, we found that Coxiella T4BSS inhibits IL-17 activation of the NF-κB and MAPK pathways and blocks IL-17-mediated oxidative stress. These findings reveal a novel strategy employed by intracellular bacteria to escape the immune response during initial stages of infection. Further identification of virulence factors involved in this mechanism will bring to light new therapeutic targets to prevent Q fever development into a chronic life-threatening endocarditis.

Dataset Information

Tissue-resident macrophages actively suppress IL-1beta release via a reactive prostanoid/IL-10 pathway.

Publications

Tissue-resident macrophages actively suppress IL-1beta release via a reactive prostanoid/IL-10 pathway.

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