Mechanisms controlling Th17 cytokine expression and host defense

McAleer, Jeremy P.; Kolls, Jay K.

doi:10.1189/jlb.0211099

Cited by 88 publications

(74 citation statements)

References 134 publications

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“…7B). We also observed a lower level of neutrophils in IL-17RA Ϫ/Ϫ naïve mice compared to WT noninfected mice, in accordance with a previous study (57) and other literature suggesting a role of IL-17 during granulopoiesis and migration of neutrophils in tissues (3,33).…”

Section: Resultssupporting

confidence: 80%

Differential Role of the Interleukin-17 Axis and Neutrophils in Resolution of Inhalational Anthrax

et al. 2012

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The roles of interleukin-17 (IL-17) and neutrophils in the lung have been described as those of two intricate but independent players. Here we identify neutrophils as the primary IL-17-secreting subset of cells in a model of inhalation anthrax using A/J and C57BL/6 mice. With IL-17 receptor A knockout (IL-17RA ؊/؊ ) mice, we confirmed that IL-17A/F signaling is instrumental in the self-recruitment of this population. We also show that the IL-17A/F axis is critical for surviving pulmonary infection, as IL-17RA ؊/؊ mice become susceptible to intranasal infection by Bacillus anthracis Sterne spores. Strikingly, infection with a fully virulent strain did not affect IL-17RA ؊/؊ mouse survival. Eventually, by depleting neutrophils in wild-type and IL-17RA ؊/؊ mice, we demonstrated the crucial role of IL-17-secreting neutrophils in mouse survival of infection by fully virulent B. anthracis. This work demonstrates the important roles of both IL-17 signaling and neutrophils in clearing this pathogen and surviving pulmonary B. anthracis infection.

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Section: Resultssupporting

confidence: 80%

Differential Role of the Interleukin-17 Axis and Neutrophils in Resolution of Inhalational Anthrax

et al. 2012

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“…The analysis of cytokine production was extended to Th1/Th2, regulatory cytokines, and IL-22, which is coexpressed with IL-17 by Th17 cells (28). We found that, besides IL-17 and IL-6, FICZ induced BMMC production of the proinflammatory IL-13 and the regulatory IL-10 cytokines.…”

Section: Ficz Stimulation Sets the Stage For The Proinflammatory Milimentioning

confidence: 90%

The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

Sibilano

Frossi

Calvaruso

et al. 2012

The Journal of Immunology

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The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor whose activity is modulated by xenobiotics as well as physiological ligands. These compounds may modulate inflammatory responses and contribute to the rising prevalence of allergic diseases observed in industrialized countries. Mast cells (MCs), located within tissues at the boundary of the external environment, represent a potential target of AhR ligands. In this study, we report that murine and human MCs constitutively express AhR, and its activation by the high-affinity ligand 6-formylindolo[3,2-b]carbazole (FICZ) determines a boost in degranulation. On the contrary, repeated exposure to FICZ inhibits MC degranulation. Accordingly, histamine release, in an in vivo passive systemic anaphylactic model, is exacerbated by a single dose and is attenuated by repetitive stimulation of AhR. FICZ-exposed MCs produce reactive oxygen species and IL-6 in response to cAMP-dependent signals. Moreover, AhR-activated MCs produce IL-17, a critical player in chronic inflammation and autoimmunity, suggesting a novel pathway for MC activation in the pathogenesis of these diseases. Indeed, histological analysis of patients with chronic obstructive pulmonary disease revealed an enrichment in AhR/IL-6 and AhR/IL-17 double-positive MCs within bronchial lamina propria. Thus, tissue-resident MCs could translate external chemical challenges through AhR by modulating allergic responses and contributing to the generation of inflammation-related diseases.

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“…A protective role of IL-17A was subsequently also shown in the clearance of pneumococcal colonization in the absence of immunization (63). Details of the Th17 protective cytokine pathway have been recently reviewed (64).…”

Section: Noncapsular Components As Immunogensmentioning

confidence: 99%

Serotype-independent pneumococcal experimental vaccines that induce cellular as well as humoral immunity

Malley

Anderson

2012

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

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For prevention of Streptococcus pneumoniae (pneumococcus) infections in infancy, protein-conjugated capsular polysaccharide vaccines provide serotype-specific, antibody-mediated immunity but do not cover all of the 90+ capsule serotypes. Therefore, microbiologists have sought protective noncapsular antigens common to all strains. Alternatively, we investigated killed cells of a noncapsulated strain, which expose many such common antigens. Given to mice intranasally, this vaccine elicits antibody-independent, CD4+ T lymphocyte-dependent accelerated clearance of pneumococci of various serotypes from the nasopharynx mediated by the cytokine IL-17A. Such immunity may reproduce the natural resistance that develops in infants before capsular antibodies arise. Given by injection, the killed cell vaccine induces bifunctional immunity: plasma antibodies protective against fatal pneumonia challenge, as well as IL-17A–mediated nasopharyngeal clearance. Human testing of this inexpensive candidate vaccine by intramuscular injection is planned. Bacterial cellular vaccines are complex—a challenge for reproducibility. However, when several known protective antigens were deleted, the killed pneumococcal vaccine was still protective. This antigenic redundancy may prevent vaccine escape variants by recombinational loss, which is frequent in pneumococcus. Biochemically defined immunogens with bifunctional activity have also been devised. These immunogens are three-component conjugates in which cell wall teichoic acid (a common antigen capable of T cell activation) is coupled to a genetic fusion of two common pneumococcal proteins: a protective surface antigen and a derivative of pneumolysin, which provides TLR4 agonist activity and induces antitoxic immunity. Such constructs induce accelerated clearance when given intranasally and induce both immune mechanisms when injected. The defined composition permits analysis of structure-function activity.

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Mechanisms controlling Th17 cytokine expression and host defense

Cited by 88 publications

References 134 publications

Differential Role of the Interleukin-17 Axis and Neutrophils in Resolution of Inhalational Anthrax

Differential Role of the Interleukin-17 Axis and Neutrophils in Resolution of Inhalational Anthrax

The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

Serotype-independent pneumococcal experimental vaccines that induce cellular as well as humoral immunity

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