Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

textabstractThe classical paradigm of tuberculosis (TB) immunity, with a central protective role for Th1 responses and IFN-γ-stimulated cellular responses, has been challenged by unsatisfactory results of vaccine strategies aimed at enhancing Th1 immunity. Moreover, preclinical TB models have shown that increasing IFN-γ responses in the lungs is more damaging to the host than to the pathogen. Type 1 interferon signaling and altered Th17 responses have also been associated with active TB, but their functional roles in TB pathogenesis remain to be established. These two host responses have been studied in more detail in autoimmune diseases (AID) and show functional interactions that are of potential interest in TB immunity. In this review, we first identify the role of type 1 interferons and Th17 immunity in TB, followed by an overview of interactions between these responses observed in systemic AID. We discuss (i) the effects of GM-CSF-secreting Th17.1 cells and type 1 interferons on CCR2+ monocytes; (ii) convergence of IL-17 and type 1 interferon signaling on stimulating B-cell activating factor production and the central role of neutrophils in this process; and (iii) synergy between IL-17 and type 1 interferons in the generation and function of tertiary lymphoid structures and the associated follicular helper T-cell responses. Evaluation of these autoimmune-related pathways in TB pathogenesis provides a new perspective on recent developments in TB research

Modulatory role of IL-17 in airway inflammation

IL-17 orchestrates the accumulation of neutrophils to sites of infection and the release of microbicidal substances, and therefore plays a critical role in the innate immune response to infection. IL-17 is also involved in certain chronic inflammatory diseases in which dysfunctional control of neutrophil accumulation and turnover constitutes an important pathogenic factor. This pro-inflammatory potential of IL-17 in host defence and in inflammatory diseases has been studied extensively. However, there is now also published evidence that IL-17 has more complex actions, including inflammation-resolving potential under certain conditions. With this in mind, the aims of this thesis were to investigate endogenous and exogenous methods to regulate the production of IL-17 and to elucidate the role that IL-17 plays in resolving ongoing inflammation. More specifically, we looked at whether the cells in the lung produce IL-17 after exposure to lipopolysaccharide (LPS) from the Gram-negative Escherichia coli bacteria, and whether anti-inflammatory pharmacotherapies could be used to regulate the production of IL-17 in these cells. We also examined whether IL-17 contributes to neutrophil turnover through the regulation of macrophage phagocytosis of apoptotic neutrophils. Finally, we investigated whether IL-17 down-regulates the release of the upstream regulator IL-23. We found that LPS induced sustained IL-17 production and release from T cells that reside in lung tissue and that are recruited to the bronchoalveolar space in a mouse model of acute inflammation in vivo. In addition, population of cells other than T cells contributed to IL-17 production in the lung tissues and in the bronchoalveolar space. LPS-induced IL-17 production from T cells in lung tissues and in the bronchoalveolar space was inhibited by the anti-inflammatory drug dexamethasone. Furthermore, we found that IL-17 stimulated macrophage phagocytosis of apoptotic neutrophils and particles, and induced neutrophil apoptosis in an in vitro study on isolated murine and human cells. Finally, we found that that IL-17 inhibited the release of the upstream regulator IL-23, both in the bronchoalveolar space in mice in vivo and in isolated human cells of the monocyte lineage. A major finding is that the production of IL-17 can be regulated exogenously by anti-inflammatory drugs and endogenously by an IL-17-induced feedback loop, which, in turn, may protect against excessive, IL-23-induced IL-17 signalling. In addition, we demonstrate that IL-17 has both pro-inflammatory and inflammation-resolving actions; IL-17 accumulates neutrophils after stimulation with LPS, while it also induces the phagocytosis of apoptotic neutrophils, thereby controlling the total turnover of neutrophils. That IL-17 induces the apoptosis of neutrophils and increases the phagocytosis of these cells indicates a potentially valuable strategy to mitigate conditions in which necrotic neutrophils are an important contributor to severe and sometimes life-threatening conditions, such as chronic lung allograft rejection and acute respiratory distress syndrome

Interleukin-17A during Local and Systemic Staphylococcus aureus-Induced Arthritis in Mice▿

Staphylococcus aureus is one of the dominant pathogens that induce septic arthritis in immunocompromised hosts, e.g., patients suffering from rheumatoid arthritis treated with immunosuppressive drugs. S. aureus-induced arthritis leads to severe joint destruction and high mortality despite antibiotic treatment. Recently, interleukin-17A (IL-17A) has been discovered to be an important mediator of aseptic arthritis both in mice and humans, but its function in S. aureus-induced arthritis is largely unknown. Here, we investigated the role of IL-17A in host defense against arthritis following systemic and local S. aureus infection in vivo. IL-17A knockout mice and wild-type mice were inoculated systemically (intravenously) or locally (intra-articularly) with S. aureus. During systemic infection, IL-17A knockout mice lost significantly more weight than the wild-type mice did, but no differences were found in the mortality rate. The absence of IL-17A had no impact on clinical arthritis development but led to increased histopathological erosivity late during systemic S. aureus infection. Bacterial clearance in kidneys was increased in IL-17A knockout mice compared to the level in wild-type mice only 1 day after bacterial inoculation. During systemic S. aureus infection, serum IL-17F protein levels and mRNA levels in the lymph nodes were elevated in the IL-17A knockout mice compared to the level in wild-type mice. In contrast to systemic infection, the IL-17A knockout mice had increased synovitis and erosions and locally decreased clearance of bacteria 3 days after local bacterial inoculation. On the basis of these findings, we suggest that IL-17A is more important in local host defense than in systemic host defense against S. aureus-induced arthritis

Negative feedback on IL-23 exerted by IL-17A during pulmonary inflammation

It is now established that IL-17 has a broad pro-inflammatory potential in mammalian host defense, in inflammatory disease and in autoimmunity, whereas little is known about its anti-inflammatory potential and inhibitory feedback mechanisms. Here, we examined whether IL-17A can inhibit the extracellular release of IL-23 protein, the upstream regulator of IL-17A producing lymphocyte subsets, that is released from macrophages during pulmonary inflammation. We characterized the effect of IL-17A on IL-23 release in several models of pulmonary inflammation, evaluated the presence of IL-17 receptor A (RA) and C (RC) on human alveolar macrophages and assessed the role of the Rho family GTPase Rac1 as a mediator of the effect of IL-17A on the release of IL-23 protein. In a model of sepsis-induced pneumonia, intravenous exposure to Staphylococcus aureus caused higher IL-23 protein concentrations in cell-free bronchoalveolar lavage (BAL) samples from IL-17A knockout (KO) mice, compared with wild type (WT) control mice. In a model of Gram-negative airway infection, pre-treatment with a neutralizing anti-IL-17A Ab and subsequent intranasal (i.n.) exposure to LPS caused higher IL-23 and IL-17A protein concentrations in BAL samples compared with mice exposed to LPS, but pre-treated with an isotype control Ab. Moreover, i.n. exposure with IL-17A protein per se decreased IL- 23 protein concentrations in BAL samples. We detected IL-17RA and IL-17RC on human alveolar macrophages, and found that in vitro stimulation of these cells with IL-17A protein, after exposure to LPS, decreased IL-23 protein in conditioned medium, but not IL-23 p19 or p40 mRNA. This study indicates that IL-17A can partially inhibit the release of IL-23 protein during pulmonary inflammation, presumably by stimulating the here demonstrated receptor units IL-17RA and IL-17RC on alveolar macrophages. Hypothetically, the demonstrated mechanism may serve as negative feedback to protect from excessive IL-17A signaling and to control antibacterial host defense once it is activated

IL-17A as a regulator of neutrophil survival in nasal polyp disease of patients with and without cystic fibrosis

AbstractNasal polyps in adults are characterized by a chronic inflammation of the upper airways and by the preferential activation of Th2 cells. In contrast, IL-17 producing Th17 cells dominate the inflammation in nasal polyps of cystic fibrosis (CF) patients.MethodIL-17A, IL-5, IL-6, IL-8, IL-1β, ECP, MCP-1 and myeloperoxidase expression was determined in tissue homogenates of nasal polyps of non-CF and CF patients and controls. The cellular source of IL-17A was determined by immuno-histochemistry and FACS analysis. The functional role of IL-17A in the survival of neutrophils from CF and non-CF patients was tested.ResultsA significant upregulation of IL-17A and myeloperoxidase could be observed in nasal polyps from CF-patients. The cellular sources of IL-17A in nasal polyps were mainly T-lymphocytes. IL-17A was able to modulate the survival of neutrophils in nasal polyps from non-CF patients; however the survival of neutrophils in CF patients was independent of IL-17A.ConclusionThe present study shows that IL-17A has an impact on neutrophil survival in adult nasal polyp disease, but not in nasal polyps from CF patients