Neutrophils Are Essential As A Source Of Il-17 In The Effector Phase Of Arthritis

Katayama, Masaki; Ohmura, Koichiro; Yukawa, Naoichiro; Terao, Chikashi; Hashimoto, Motomu; Yoshifuji, Hajime; Kawabata, Daisuke; Fujii, Tomoyuki; Iwakura, Yoichiro; Mimori, Tsuneyo

doi:10.1371/journal.pone.0062231

Cited by 67 publications

(58 citation statements)

References 25 publications

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“…IL-17RA −/− mice develop less severe arthritis, and expression of several pro-inflammatory mediators are decreased in the ankle joints (36). A similar finding is shown in IL-17 −/− mice, where neutrophils are shown to be an important source of IL-17 production (37). It is important to note that arthritis in the serum transfer model is much less aggressive than in the spontaneous K/BxN model due to the much lower titers of autoantibodies transferred.…”

Section: Discussionsupporting

confidence: 80%

Gut Microbiota Regulates K/BxN Autoimmune Arthritis through Follicular Helper T but Not Th17 Cells

Block

Zheng

Dent

et al. 2016

The Journal of Immunology

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The bacterial community that colonizes mucosal surfaces helps shape the development and function of the immune system. The K/BxN autoimmune arthritis model is dependent on the microbiota, and particularly on segmented filamentous bacteria (SFB), for the autoimmune phenotype. The mechanisms of how the gut microbiota affects arthritis development are not well understood. Here we investigate the contribution of two T cell subsets, Th17 and Tfh, to arthritis and how microbiota modulates their differentiation. Using genetic approaches, we demonstrate that IL-17 is dispensable for arthritis. Antibiotic treatment inhibits disease in IL-17 deficient animals suggesting that the gut microbiota regulates arthritis independent of Th17 cells. In contrast, conditional deletion of Bcl6 in T cells blocks Tfh cell differentiation and arthritis development. Furthermore, Tfh cell differentiation is defective in antibiotic-treated mice. Taken together, we conclude that gut microbiota regulates arthritis through Tfh but not Th17 cells. These findings have implications in our understanding of how environmental factors contribute to the development of autoimmune diseases.

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Section: Discussionsupporting

confidence: 80%

Gut Microbiota Regulates K/BxN Autoimmune Arthritis through Follicular Helper T but Not Th17 Cells

Block

Zheng

Dent

et al. 2016

The Journal of Immunology

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“…Recently, immune complexes present during acute arthritis were shown to induce IL-17 production by neutrophils (65). Similar levels of neutralizing antibody responses were raised against CHIKV in WT and CCR2…”

Section: This Paper Describes the First Analysis Of Viral Arthritis Imentioning

confidence: 77%

CCR2 Deficiency Promotes Exacerbated Chronic Erosive Neutrophil-Dominated Chikungunya Virus Arthritis

Poo

Nakaya

Gardner

et al. 2014

J Virol

122

143

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Chikungunya virus (CHIKV) is a member of a globally distributed group of arthritogenic alphaviruses that cause weeks to months of debilitating polyarthritis/arthralgia, which is often poorly managed with current treatments. Arthritic disease is usually characterized by high levels of the chemokine CCL2 and a prodigious monocyte/macrophage infiltrate. Several inhibitors of CCL2 and its receptor CCR2 are in development and may find application for treatment of certain inflammatory conditions, including autoimmune and viral arthritides. Here we used CCR2 ؊/؊ mice to determine the effect of CCR2 deficiency on CHIKV infection and arthritis. Although there were no significant changes in viral load or RNA persistence and only marginal changes in antiviral immunity, arthritic disease was substantially increased and prolonged in CCR2 ؊/؊ mice compared to wild-type mice. The monocyte/macrophage infiltrate was replaced in CCR2 ؊/؊ mice by a severe neutrophil (followed by an eosinophil) infiltrate and was associated with changes in the expression levels of multiple inflammatory mediators (including CXCL1, CXCL2, granulocyte colony-stimulating factor [G-CSF], interleukin-1␤ [IL-1␤], and IL-10). The loss of anti-inflammatory macrophages and their activities (e.g., efferocytosis) was also implicated in exacerbated inflammation. Clear evidence of cartilage damage was also seen in CHIKV-infected CCR2 ؊/؊ mice, a feature not normally associated with alphaviral arthritides. Although recruitment of CCR2 ؉ monocytes/macrophages can contribute to inflammation, it also appears to be critical for preventing excessive pathology and resolving inflammation following alphavirus infection. Caution might thus be warranted when considering therapeutic targeting of CCR2/CCL2 for the treatment of alphaviral arthritides. IMPORTANCEHere we describe the first analysis of viral arthritis in mice deficient for the chemokine receptor CCR2. CCR2 is thought to be central to the monocyte/macrophage-dominated inflammatory arthritic infiltrates seen after infection with arthritogenic alphaviruses such as chikungunya virus. Surprisingly, the viral arthritis caused by chikungunya virus in CCR2-deficient mice was more severe, prolonged, and erosive and was neutrophil dominated, with viral replication and persistence not being significantly affected. Monocytes/macrophages recruited by CCL2 thus also appear to be important for both preventing even worse pathology mediated by neutrophils and promoting resolution of inflammation. Caution might thus be warranted when considering the use of therapeutic agents that target CCR2/CCL2 or inflammatory monocytes/macrophages for the treatment of alphaviral (and perhaps other viral) arthritides. Individuals with diminished CCR2 responses (due to drug treatment or other reasons) may also be at risk of exacerbated arthritic disease following alphaviral infection.

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“…34 IL-17-producing ILCs were also reported to determine protection against C. albicans in a murine model of oropharyngeal candidiasis. 33 Even neutrophils can be a source of IL-17, 35 and their importance in a model of keratitis by Aspergillus was also documented. 36 In conclusion, our findings add T.rubrum as another NLRP3 inflammasome activator, supporting this system as another component of the inflammatory process in dermatophytosis.…”

Section: Discussionmentioning

confidence: 96%

IL-1 signaling inhibits Trichophyton rubrum conidia development and modulates the IL-17 response in vivo

2015

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Dermatophytosis are one of the most common fungal infections in the world. They compromise keratinized tissues and the main etiological agent is Trichophyton rubrum. Macrophages are key cells in innate immunity and prominent sources of IL-1b, a potent inflammatory cytokine whose main production pathway is by the activation of inflammasomes and caspase-1. However, the role of inflammasomes and IL-1 signaling against T.rubrum has not been reported. In this work, we observed that bone marrow-derived macrophages produce IL-1b in response to T.rubrum conidia in a NLRP3-, ASC-and caspase-1-dependent fashion. Curiously, lack of IL-1 signaling promoted hyphae development, uncovering a protective role for IL-1b in macrophages. In addition, mice lacking IL-1R showed reduced IL-17 production, a key cytokine in the antifungal defense, in response to T.rubrum. Our findings point to a prominent role of IL-1 signaling in the immune response to T.rubrum, opening the venue for the study of this pathway in other fungal infections.

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Neutrophils Are Essential As A Source Of Il-17 In The Effector Phase Of Arthritis

Cited by 67 publications

References 25 publications

Gut Microbiota Regulates K/BxN Autoimmune Arthritis through Follicular Helper T but Not Th17 Cells

Gut Microbiota Regulates K/BxN Autoimmune Arthritis through Follicular Helper T but Not Th17 Cells

CCR2 Deficiency Promotes Exacerbated Chronic Erosive Neutrophil-Dominated Chikungunya Virus Arthritis

IL-1 signaling inhibits Trichophyton rubrum conidia development and modulates the IL-17 response in vivo

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