Interleukin-17A (IL-17A) and IL-17F Are Critical for Antimicrobial Peptide Production and Clearance of Staphylococcus aureus Nasal Colonization

Archer, Nathan K.; Adappa, Nithin D.; Palmer, James N.; Cohen, Noam A.; Harro, Jan; Lee, Steven K.; Miller, Lloyd S.; Shirtliff, Mark E.

doi:10.1128/iai.00596-16

Cited by 62 publications

(61 citation statements)

References 51 publications

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“…The marked increase in neutrophil infiltration as well as production of Th17 cytokines IL-17 and IL-22 in influenza-infected T-bet À/À lungs at a timepoint where hosts are most susceptible to bacterial infection (Sun & Metzger, 2008;Chertow & Memoli, 2013) prompted us to examine antibacterial defences of T-bet-deficient hosts during secondary infection. While IL-17 has also been shown to induce antibacterial defence through upregulating antimicrobial peptides (Liang et al, 2006;Archer et al, 2016), our observation that there is no considerable increased expression in T-bet À/À lungs at day 3 post-bacterial infection suggests that this mechanism may only be applicable to early bacterial load control. We found that decreased bacterial load in T-bet À/À superinfected lungs and increased survival were attributable to IL-17-mediated neutrophil recruitment.…”

Section: Of 16mentioning

confidence: 76%

Loss of T‐bet confers survival advantage to influenza–bacterial superinfection

Koean

Ding

2018

The EMBO Journal

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The transcription factor, T‐bet, regulates type 1 inflammatory responses against a range of infections. Here, we demonstrate a previously unaddressed role of T‐bet, to influenza virus and bacterial superinfection. Interestingly, we found that T‐bet deficiency did not adversely affect the efficacy of viral clearance or recovery compared to wild‐type hosts. Instead, increased infiltration of neutrophils and production of Th17 cytokines (IL‐17 and IL‐22), in lungs of influenza virus‐infected T‐bet−/− mice, were correlated with survival advantage against subsequent infection by Streptococcus pneumoniae. Neutralization of IL‐17, but not IL‐22, in T‐bet−/− mice increased pulmonary bacterial load, concomitant with decreased neutrophil infiltration and reduced survival of T‐bet−/− mice. IL‐17 production by CD8+, CD4+ and γδ T cell types was identified to contribute to this protection against bacterial superinfection. We further showed that neutrophil depletion in T‐bet−/− lungs increased pulmonary bacterial burden. These results thus indicate that despite the loss of T‐bet, immune defences required for influenza viral clearance are fully functional, which in turn enhances protective type 17 immune responses against lethal bacterial superinfections.

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Section: Of 16mentioning

confidence: 76%

Loss of T‐bet confers survival advantage to influenza–bacterial superinfection

Koean

Ding

2018

The EMBO Journal

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“…The IL17 family of cytokines has been linked to the pathogenesis of diverse autoimmune and inflammatory diseases and also plays an essential role in host defence against extracellular bacteria and fungi . IL17A has also been shown to increase the expression of skin antimicrobial peptides including HBD2, psoriasin (S100A7) and calprotectin (S100A8/9) in keratinocytes and also a number of CXC chemokines, which are neutrophil attractants such as CXCL1, CXCL3, CXCL5 and IL8 . Thus, IL17A may contribute to inflammation by increasing the influx of neutrophils, dendritic cells and memory T cells into the lesion.…”

Section: Discussionmentioning

confidence: 99%

Alterations in innate immunity and epithelial cell differentiation are the molecular pillars of hidradenitis suppurativa

Zouboulis

Costa

Makrantonaki

et al. 2020

Acad Dermatol Venereol

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Background The large unmet need of hidradenitis suppurativa/acne inversa (HS) therapy requires the elucidation of disease‐driving mechanisms and tissue targeting. Objective Robust characterization of the underlying HS mechanisms and detection of the involved skin compartments. Methods Hidradenitis suppurativa/acne inversa molecular taxonomy and key signalling pathways were studied by whole transcriptome profiling. Dysregulated genes were detected by comparing lesional and non‐lesional skin obtained from female HS patients and matched healthy controls using the Agilent array platform. The differential gene expression was confirmed by quantitative real‐time PCR and targeted protein characterization via immunohistochemistry in another set of female patients. HS‐involved skin compartments were also recognized by immunohistochemistry. Results Alterations to key regulatory pathways involving glucocorticoid receptor, atherosclerosis, HIF1α and IL17A signalling as well as inhibition of matrix metalloproteases were detected. From a functional standpoint, cellular assembly, maintenance and movement, haematological system development and function, immune cell trafficking and antimicrobial response were key processes probably being affected in HS. Sixteen genes were found to characterize HS from a molecular standpoint (DEFB4, MMP1, GJB2, PI3, KRT16, MMP9, SERPINB4, SERPINB3, SPRR3, S100A8, S100A9, S100A12, S100A7A (15), KRT6A, TCN1, TMPRSS11D). Among the proteins strongly expressed in HS, calgranulin‐A, calgranulin‐B and serpin‐B4 were detected in the hair root sheath, koebnerisin and connexin‐32 in stratum granulosum, transcobalamin‐1 in stratum spinosum/hair root sheath, small prolin‐rich protein‐3 in apocrine sweat gland ducts/sebaceous glands‐ducts and matrix metallopeptidase‐9 in resident monocytes. Conclusion Our findings highlight a panel of immune‐related drivers in HS, which influence innate immunity and cell differentiation in follicular and epidermal keratinocytes as well as skin glands.

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“…With the emergent data from genetics and imaging and therapy, the immunological focus of IL‐23 pathway research in the skeleton is now firmly pointed at the enthesis. It is understandable that the skin and gut have an IL‐23/17 axis for fighting infection and also for participation in tissue repair . The normal enthesis is protected from the outside world so it is likely that the presence of the IL‐23/17 axis cells and cytokines at this site is likely to have a physiological role in tissue repair.…”

Section: Animal Models Showing a Role For Il‐23 In Enthesitismentioning

confidence: 99%

“…It is understandable that the skin and gut have an IL-23/17 axis for fighting infection and also for participation in tissue repair. 241,242 The normal enthesis is protected from the outside world so it is likely that the presence of the IL-23/17 axis cells and cytokines at this site is likely to have a physiological role in tissue repair.…”

Section: Unraveling Role Of Il-23 In Enthesis Biologymentioning

confidence: 99%

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

Bridgewood

Sharif

Sherlock

et al. 2020

Immunological Reviews

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The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL‐23R or the interleukin‐23 (IL‐23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin‐17 (IL‐17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL‐23R–expressing cells were ensconced in healthy murine enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL‐23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL‐23R–expressing myeloid cells and various innate and adaptive T cells that produce IL‐17 family cytokines have also been described in the human enthesis. Blockade of IL‐23 pathway with either anti‐p40 or anti‐p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL‐23 at the human enthesis and highlight the remarkable emerging story of this unique skeletal tissue.

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Interleukin-17A (IL-17A) and IL-17F Are Critical for Antimicrobial Peptide Production and Clearance of Staphylococcus aureus Nasal Colonization

Cited by 62 publications

References 51 publications

Loss of T‐bet confers survival advantage to influenza–bacterial superinfection

Loss of T‐bet confers survival advantage to influenza–bacterial superinfection

Alterations in innate immunity and epithelial cell differentiation are the molecular pillars of hidradenitis suppurativa

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

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