Interleukin-17A during Local and Systemic Staphylococcus aureus-Induced Arthritis in Mice (original) (raw)
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Infection and immunity, 2015
Staphylococcus aureus is the leading cause of skin and skin structure infections (SSSI) in humans. Moreover, the high frequency of recurring SSSI due to S. aureus, particularly methicillin-resistant strains (MRSA), suggests infection induces suboptimal anamnestic defenses. The present study addresses the hypothesis that interleukin-17A (IL-17A) and IL-22 play distinct roles in immunity to cutaneous and invasive MRSA infection in a mouse model of SSSI. Mice were treated with specific neutralizing antibodies against IL-17A and/or IL-22 and infected with MRSA after which the severity of infection and host immune response were determined. Neutralization of either IL-17A or IL-22 individually reduced T cell and neutrophil infiltration, and host defense peptide elaboration in lesions. These events corresponded with increased abscess severity, MRSA viability and CFU density in skin. Interestingly, combined inhibition of IL-17A and IL-22 did not worsen abscesses, but increased interferon-γ ...
Interleukin-17 acts independently of TNF-alpha under arthritic conditions
Journal of immunology (Baltimore, Md. : 1950), 2006
The proinflammatory T cell cytokine IL-17 is a potent inducer of other cytokines such as IL-1 and TNF-alpha. The contribution of TNF in IL-17-induced joint inflammation is unclear. In this work we demonstrate using TNF-alpha-deficient mice that TNF-alpha is required in IL-17-induced joint pathology under naive conditions in vivo. However, overexpression of IL-17 aggravated K/BxN serum transfer arthritis to a similar degree in TNF-alpha-deficient mice and their wild-type counterparts, indicating that the TNF dependency of IL-17-induced pathology is lost under arthritic conditions. Also, during the course of the streptococcal cell wall-induced arthritis model, IL-17 was able to enhance inflammation and cartilage damage in the absence of TNF. Additional blocking of IL-1 during IL-17-enhanced streptococcal cell wall-induced arthritis did not reduce joint pathology in TNF-deficient mice, indicating that IL-1 is not responsible for this loss of TNF dependency. These data provide further u...
Infections with Staphylococcus aureus are a continuing and growing problem in community and hospital settings. Preclinical animal modeling of S. aureus relies on experimental infection, which carries some limitations. We describe here a novel, spontaneous model of oral staphylococcal infection in double knockout mice, deficient in the receptors for IL-17 (IL-17RA) and interferon (IFN)-g (IFNgRI), beginning at 6 to 8 weeks of age. IFNgRI À/À IL17RA À/À (GRAKO) mice developed progressive oral abscesses. Cytometric methods revealed extensive neutrophilic infiltration of oral tissues in GRAKO mice; further investigation evidenced that IL-17 predominated neutrophil defects in these mice. To investigate the contribution of IFN-g signaling to this native host defense to S. aureus, we observed perturbations of monocyte recruitment and macrophage differentiation in the oral tissues of GRAKO mice, and CXCL9/ chemokine ligand receptor (CXCR)3-driven recruitment of T-cell oral tissues and draining lymph nodes. To address the former finding, we depleted macrophages and monocytes in vivo from IL17RA À/À mice using liposomes loaded with clodronate. This treatment elicited oral abscesses, recapitulating the phenotype of GRAKO mice. From these findings, we propose novel collaborative functions of IL-17 and IFN-g, acting through neutrophils and macrophages, respectively, in native mucocutaneous host defenses to S. aureus. (Am J Pathol 2016,-: 1e16; http://dx.doi.org/10.1016/j.ajpath.2016.07.001)
Scientific Reports
Interleukin-17A (IL-17A) is considered an important pro-inflammatory cytokine but its importance in joint diseases such as rheumatoid arthritis (RA) is unclear. It has also been reported that IL-17A may induce pain but it is unclear whether pro-inflammatory and pro-nociceptive effects are linked. Here we studied in wild type (WT) and IL-17A knockout (IL-17AKO) mice inflammation and hyperalgesia in antigen-induced arthritis (AIA). We found that the severity and time course of AIA were indistinguishable in WT and IL-17AKO mice. Furthermore, the reduction of inflammation by sympathectomy, usually observed in WT mice, was preserved in IL-17AKO mice. Both findings suggest that IL-17A is redundant in AIA pathology. However, in the course of AIA IL-17AKO mice showed less mechanical hyperalgesia than WT mice indicating that IL-17A contributes to pain even if it is not crucial for arthritis pathology. In support for a role of IL-17A and other members of the IL-17 family in the generation of pain we found that sensory neurones in the dorsal root ganglia (DRG) express all IL-17 receptor subtypes. Furthermore, in isolated DRG neurones most IL-17 isoforms increased tetrodotoxin-(TTX-) resistant sodium currents which indicate a role of IL-17 members in inflammation-evoked sensitization of sensory nociceptive neurones. Interleukin-17A (IL-17A), before 2003 in the context of autoimmune diseases commonly only called IL-17, and five additional cytokines (IL-17B-F) form a family of closely related cytokines 1, 2. IL-17A, the prototype member of the IL-17 family 3 , is secreted from Th17, CD8 + T, γ∂T, natural killer cells, activated monocytes and neutrophils 3. As a mediator of both innate and adaptive immunity 2, 4, 5 , IL-17 is involved in the defence against bacteria and fungi 6, 7 as well as in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis, and others 2-5. Drugs targeting "IL-17 signalling" are in preclinical development and clinical trials for the treatment of chronic inflammatory disorders 8. However, particularly in RA, the role of IL-17 is not well understood. The inflamed synovium of RA patients contains plenty of Th17 cells and the IL-17 levels in the synovial fluid correlate with disease severity 9, 10. IL-17A induces the release of chemokines and cytokines (IL-1β, IL-6, IL-8, RANKL, TNF), matrix metalloproteinases, nitric oxide and prostaglandin E 2 from fibroblasts, osteoblasts, chondrocytes and macrophages, all cells involved in RA pathogenesis 9, 11-14. However, secukinumab, an antibody against IL-17A, is only approved for the treatment of psoriasis arthritis and ankylosing spondylitis while IL-17A neutralisation in RA had less convincing clinical effects so far 15. Interestingly, in experimental mouse models of arthritis the pathogenic role of IL-17 is also heterogeneous. While collagen-induced arthritis (CIA) depends on the presence of IL-17 16 , K/BxN serum-transfer arthritis 17 ,
The nature of innate and adaptive interleukin-17A responses in sham or bacterial inoculation
Immunology, 2012
Streptococcus pyogenes is the causative agent of numerous diseases ranging from benign infections (pharyngitis and impetigo) to severe infections associated with high mortality (necrotizing fasciitis and bacterial sepsis). As with other bacterial infections, there is considerable interest in characterizing the contribution of interleukin-17A (IL-17A) responses to protective immunity. We here show significant il17a up-regulation by quantitative real-time PCR in secondary lymphoid organs, correlating with increased protein levels in the serum within a short time of S. pyogenes infection. However, our data offer an important caveat to studies of IL-17A responsiveness following antigen inoculation, because enhanced levels of IL-17A were also detected in the serum of sham-infected mice, indicating that inoculation trauma alone can stimulate the production of this cytokine. This highlights the potency and speed of innate IL-17A immune responses after inoculation and the importance of proper and appropriate controls in comparative analysis of immune responses observed during microbial infection.