IL-33 Signaling Regulates Innate IL-17A and IL-22 Production via Suppression of Prostaglandin E2 during Lung Fungal Infection

Garth, Jaleesa M.; Reeder, Kristen M.; Godwin, Matthew S.; Mackel, Joseph J; Dunaway, Chad W.; Blackburn, Jonathan P.; Steele, Chad

doi:10.4049/jimmunol.1602186

Cited by 35 publications

(38 citation statements)

References 51 publications

(71 reference statements)

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“…fumigatus challenge. In our report with IL-33 receptor-deficient mice, enhanced prostaglandin E 2 (PGE 2 ) production drove the observed elevations in IL-17A and IL-22 levels at 48 h postchallenge (32). We similarly observed elevated production of PGE 2 by lung cells from Chia Ϫ/Ϫ mice compared to WT mice at 48 h postchallenge ( Fig.…”

Section: Resultssupporting

confidence: 53%

“…human peripheral blood mononuclear cell (PBMC) cultures may induce the antiinflammatory cytokine IL-1RA (30) or that A. fumigatus chitin is essentially inert (31). We recently reported that mice deficient in the receptor for the IL-1 family cytokine IL-33 demonstrated similarly enhanced A. fumigatus lung clearance in the absence of changes in lung cellularity (32). Mechanistically, we demonstrated this phenotype was a result of increased IL-1␣, IL-1␤, IL-6, IL-17A, and IL-22 production (32).…”

Section: Resultsmentioning

confidence: 99%

“…We recently reported that mice deficient in the receptor for the IL-1 family cytokine IL-33 demonstrated similarly enhanced A. fumigatus lung clearance in the absence of changes in lung cellularity (32). Mechanistically, we demonstrated this phenotype was a result of increased IL-1␣, IL-1␤, IL-6, IL-17A, and IL-22 production (32). In accordance with this, despite the lower fungal burden at 48 h, Chia Ϫ/Ϫ mice also demonstrated elevated IL-1␣ ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Although opposite our hypothesis, the ϳ3-fold decrease in the fungal burden between wild-type and AMCase-deficient mice at 2 days postchallenge is of a magnitude comparable to that in our previous studies employing mice on the C57BL/6 background. Susceptible Dectin-1-deficient mice demonstrate ϳ3to 5-foldhigher burdens and significant associated mortality (45), whereas resistant IL-33 receptor (IL-33R)-deficient mice have ϳ4to 5-fold-lower burdens (32). Examination of changes in the immune responses between WT and Chia Ϫ/Ϫ mice at 2 days postexposure demonstrated the enhanced production of a specific set of inflammatory mediators.…”

Section: Discussionmentioning

confidence: 99%

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Acidic Mammalian Chitinase Negatively Affects Immune Responses during Acute and Chronic Aspergillus fumigatus Exposure

et al. 2018

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Chitin is a polysaccharide that provides structure and rigidity to the cell walls of fungi and insects. Mammals possess multiple chitinases, which function to degrade chitin, thereby supporting a role for chitinases in immune defense. However, chitin degradation has been implicated in the pathogenesis of asthma. Here, we determined the impact of acidic mammalian chitinase (AMCase) () deficiency on host defense during acute exposure to the fungal pathogen as well as its contribution to-associated allergic asthma. We demonstrate that chitin in the fungal cell wall was detected at low levels in conidia, which emerged at the highest level during hyphal transition. In response to acute challenge, mice unexpectedly demonstrated lower lung burdens at 2 days postchallenge. The lower fungal burden correlated with decreased lung interleukin-33 (IL-33) levels yet increased IL-1β and prostaglandin E (PGE) production, a phenotype that we reported previously to promote the induction of IL-17A and IL-22. During chronic exposure, AMCase deficiency resulted in lower dynamic and airway lung resistance than in wild-type mice. Improved lung physiology correlated with attenuated levels of the proallergic chemokines CCL17 and CCL22. Surprisingly, examination of inflammatory responses during chronic exposure revealed attenuated IL-17A and IL-22 responses, but not type 2 responses, in the absence of AMCase. Collectively, these data suggest that AMCase functions as a negative regulator of immune responses during acute fungal exposure and is a contributor to fungal asthma severity, putatively via the induction of proinflammatory responses.

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Section: Resultssupporting

confidence: 53%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Acidic Mammalian Chitinase Negatively Affects Immune Responses during Acute and Chronic Aspergillus fumigatus Exposure

et al. 2018

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“…Our studies demonstrate that tipping the IL-22/IL-22BP axis in favor of IL-22 is beneficial during influenza infection. Furthermore, targeting this axis has also proven useful in lung bacterial infections 4,19 and fungal infections, 46 as well as bacterial co-infections. 8,22 The question remains though-If IL-22 is so important in resolving infection, why is it so tightly controlled and is it safe to target?…”

Section: Discussionmentioning

confidence: 99%

Targeting the IL-22/IL-22BP axis enhances tight junctions and reduces inflammation during influenza infection

et al. 2020

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The seasonal burden of influenza coupled with the pandemic outbreaks of more pathogenic strains underscore a critical need to understand the pathophysiology of influenza injury in the lung. Interleukin-22 (IL-22) is a promising cytokine that is critical in protecting the lung during infection. This cytokine is strongly regulated by the soluble receptor IL-22-binding protein (IL-22BP), which is constitutively expressed in the lungs where it inhibits IL-22 activity. The IL-22/IL-22BP axis is thought to prevent chronic exposure of epithelial cells to IL-22. However, the importance of this axis is not understood during an infection such as influenza.Here we demonstrate through the use of IL-22BP-knockout mice (il-22ra2 −/− ) that a pro-IL-22 environment reduces pulmonary inflammation during H1N1 (PR8/34 H1N1) infection and protects the lung by promoting tight junction formation. We confirmed these results in normal human bronchial epithelial cells in vitro demonstrating improved membrane resistance and induction of the tight junction proteins Cldn4, Tjp1, and Tjp2. Importantly, we show that administering recombinant IL-22 in vivo reduces inflammation and fluid leak into the lung. Taken together, our results demonstrate the IL-22/IL-22BP axis is a potential targetable pathway for reducing influenza-induced pneumonia.Mucosal Immunology (2020) 13:64-74; https://doi.

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Influenza A virus directly modulates mouse eosinophil responses

LeMessurier

Rooney

Ghoneim

et al. 2020

Journal of Leukocyte Biology

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Allergic asthma and influenza are common respiratory diseases with a high probability of co‐occurrence. During the 2009 influenza pandemic, hospitalized patients with influenza experienced lower morbidity if asthma was an underlying condition. We have previously demonstrated that acute allergic asthma protects mice from severe influenza and have implicated eosinophils in the airways of mice with allergic asthma as participants in the antiviral response. However, very little is known about how eosinophils respond to direct exposure to influenza A virus (IAV) or the microenvironment in which the viral burden is high. We hypothesized that eosinophils would dynamically respond to the presence of IAV through phenotypic, transcriptomic, and physiologic changes. Using our mouse model of acute fungal asthma and influenza, we showed that eosinophils in lymphoid tissues were responsive to IAV infection in the lungs and altered surface expression of various markers necessary for cell activation in a niche‐specific manner. Siglec‐F expression was altered in a subset of eosinophils after virus exposure, and those expressing high Siglec‐F were more active (IL‐5RαhiCD62Llo). While eosinophils exposed to IAV decreased their overall transcriptional activity and mitochondrial oxygen consumption, transcription of genes encoding viral recognition proteins, Ddx58 (RIG‐I), Tlr3, and Ifih1 (MDA5), were up‐regulated. CD8+ T cells from IAV‐infected mice expanded in response to IAV PB1 peptide‐pulsed eosinophils, and CpG methylation in the Tbx21 promoter was reduced in these T cells. These data offer insight into how eosinophils respond to IAV and help elucidate alternative mechanisms by which they regulate antiviral immune responses during IAV infection.

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IL-33 Signaling Regulates Innate IL-17A and IL-22 Production via Suppression of Prostaglandin E2 during Lung Fungal Infection

Cited by 35 publications

References 51 publications

Acidic Mammalian Chitinase Negatively Affects Immune Responses during Acute and Chronic Aspergillus fumigatus Exposure

Acidic Mammalian Chitinase Negatively Affects Immune Responses during Acute and Chronic Aspergillus fumigatus Exposure

Targeting the IL-22/IL-22BP axis enhances tight junctions and reduces inflammation during influenza infection

Influenza A virus directly modulates mouse eosinophil responses

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