Interleukin-17A- (IL-17A) and IL-17F-producing CD4
T helper cells (T
17 cells) are implicated in the development of chronic inflammatory diseases, such as multiple sclerosis and its animal model, ...experimental autoimmune encephalomyelitis (EAE). T
17 cells also orchestrate leukocyte invasion of the central nervous system (CNS) and subsequent tissue damage. However, the role of IL-17A and IL-17F as effector cytokines is still confused with the encephalitogenic function of the cells that produce these cytokines, namely, T
17 cells, fueling a long-standing debate in the neuroimmunology field. Here, we demonstrated that mice deficient for IL-17A/F lose their susceptibility to EAE, which correlated with an altered composition of their gut microbiota. However, loss of IL-17A/F in T
cells did not diminish their encephalitogenic capacity. Reconstitution of a wild-type-like intestinal microbiota or reintroduction of IL-17A specifically into the gut epithelium of IL-17A/F-deficient mice reestablished their susceptibility to EAE. Thus, our data demonstrated that IL-17A and IL-17F are not encephalitogenic mediators but rather modulators of intestinal homeostasis that indirectly alter CNS-directed autoimmunity.
The role of IL-17 in CNS diseases Waisman, Ari; Hauptmann, Judith; Regen, Tommy
Acta neuropathologica,
05/2015, Letnik:
129, Številka:
5
Journal Article
Recenzirano
Cytokines of the IL-17 family are uniquely placed on the border between immune cells and tissue. Although IL-17 was originally found to induce the activation and mobilization of neutrophils to sites ...of inflammation, its tissue-specific function is not yet fully understood. The best-studied IL-17 family members, IL-17A and IL-17F, are both typically produced by immune cells such as Th17, γδ T cells and innate lymphoid cells group 3. However, the cells that respond to these cytokines are mostly found in inflamed tissue. As seen in psoriatic skin lesions or in joints of rheumatoid arthritis patients, high levels of IL-17 have been detected in the central nervous system (CNS) during inflammatory responses. Here, we provide a general review of the molecular function of IL-17 and its role in the CNS in particular. Of the different inflammatory conditions of the CNS, we found multiple sclerosis (MS) to be the one most associated with the presence of Th17 cells and IL-17. In particular, many studies using the murine model for MS, experimental autoimmune encephalomyelitis, found a clear association of Th17 and IL-17 with disease severity and progression. We summarize the recent advances made in correlating the presence of IL-17 with impaired blood–brain barrier integrity as well as the activation of astrocytes and microglia and the consequences for disease progression. There is also evidence that IL-17 plays a pathogenic role in the post-ischemic phase of stroke as well as its experimental model. We review the limited but promising data on the sources of post-stroke IL-17 production and its effects on CNS-resident target cells. In addition to MS and stroke, there is also evidence linking high levels of IL-17 to depression, as a frequent comorbidity of several inflammatory diseases, as well as to different types of infections of the CNS. The evidence we supply here suggests that inhibiting the function of the IL-17 cytokine family could have a beneficial effect on pathogenic conditions in the CNS.
Interleukin-1 (IL-1) plays a crucial role in numerous inflammatory diseases via action on its only known signaling IL-1 receptor type 1 (IL-1R1). To investigate the role of IL-1 signaling in selected ...cell types, we generated a new mouse strain in which exon 5 of the Il1r1 gene is flanked by loxP sites. Crossing of these mice with CD4-Cre transgenic mice resulted in IL-1R1 loss of function specifically in T cells. These mice, termed IL-1R1ΔT, displayed normal development under steady state conditions. Importantly, isolated CD4 positive T cells retained their capacity to differentiate toward Th1 or Th17 cell lineages in vitro, and strongly proliferated in cultures supplemented with either anti-CD3/CD28 or Concanavalin A, but, as predicted, were completely unresponsive to IL-1β administration. Furthermore, IL-1R1ΔT mice were protected from gut inflammation in the anti-CD3 treatment model, due to dramatically reduced frequencies and absolute numbers of IL-17A and interferon (IFN)-γ producing cells. Taken together, our data shows the necessity of intact IL-1 signaling for survival and expansion of CD4 T cells that were developed in an otherwise IL-1 sufficient environment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lassa virus (LASV), the causative agent of Lassa fever (LF), is endemic in West Africa, accounting for substantial morbidity and mortality. In spite of ongoing research efforts, LF pathogenesis and ...mechanisms of LASV immune control remain poorly understood. While normal laboratory mice are resistant to LASV, we report that mice expressing humanized instead of murine MHC class I (MHC-I) failed to control LASV infection and develop severe LF. Infection of MHC-I knockout mice confirmed a key role for MHC-I-restricted T cell responses in controlling LASV. Intriguingly we found that T cell depletion in LASV-infected HHD mice prevented disease, irrespective of high-level viremia. Widespread activation of monocyte/macrophage lineage cells, manifest through inducible NO synthase expression, and elevated IL-12p40 serum levels indicated a systemic inflammatory condition. The absence of extensive monocyte/macrophage activation in T cell-depleted mice suggested that T cell responses contribute to deleterious innate inflammatory reactions and LF pathogenesis. Our observations in mice indicate a dual role for T cells, not only protecting from LASV, but also enhancing LF pathogenesis. The possibility of T cell-driven enhancement and immunopathogenesis should be given consideration in future LF vaccine development.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract In the central nervous system inflammation is mediated by microglia and astrocytes. To investigate its regulation, murine astrocyte cultures were treated with bacterial lipopolysaccharides ...(LPS) and analyzed with Affymetrix gene array, qRT-PCR and ELISA. Cells responded to LPS with a strong upregulation of pro-inflammatory cytokines and chemokines. Treatment with the transcriptional activator retinoic acid (RA) suppressed mRNA expression and protein release of several important cytokines (IL-1β 4%, IL-6 21%, TNFα 30%, IL-12p40 42%, and IL-12p35/p40 27%; p < 0.01). The data are consistent with the hypothesis that all- trans RA takes part in endogenous anti-inflammatory feedback loops in the CNS.
Abstract Toll-like receptor (TLR) 4 responds to a range of agonists in infection and injury, but is best known for the recognition of bacterial lipopolysaccharides (LPS). Assembly in heterologous ...receptor complexes as well as signaling through both MyD88 and TRIF adaptor proteins, as unmatched by other TLRs, could underlie its versatile response options, probably also in a cell type-dependent manner. We show that microglia, the CNS macrophages, react to diverse LPS variants, including smooth (S) and rough (R) LPS chemotypes, with cytokine/chemokine induction, MHC I expression and suppression of myelin phagocytosis. The TLR4 co-receptor CD14 was shown in peritoneal macrophages to be essential for S-LPS effects and the link of both S- and R-LPS to TRIF signaling. In contrast, cd14−/− microglia readily respond to S- and R-LPS, suggesting an a priori high(er) sensitivity to both chemotypes, while CD14 confers increased S- and R-LPS potencies and compensates for their differences. Importantly, CD14 controls the magnitude and shapes the profile of cyto/chemokine production, this influence being itself regulated by critical LPS concentrations. Comparing reactive phenotypes of microglia with deficiencies in CD14, MyD88 and TRIF ( cd14−/− , myd88−/− , and triflps2 ), we found that distinct signaling routes organize for individual functions in either concerted or non-redundant fashion and that CD14 has contributions beyond the link to TRIF. Modulation of response profiles by key cytokines finally reveals that the microglial TLR4 can differentiate between the class of LPS structures and a self-derived agonist, fibronectin. It thus proves as a sophisticated decision maker in infectious and non-infectious CNS challenges.
Aicardi-Goutières syndrome (AGS) is a rare early onset childhood encephalopathy caused by persistent neuroinflammation of autoimmune origin. AGS is a genetic disorder and >50% of affected individuals ...bear hypomorphic mutations in ribonuclease H2 (RNase H2). All available RNase H2 mouse models so far fail to mimic the prominent CNS involvement seen in AGS. To establish a mouse model recapitulating the human disease, we deleted RNase H2 specifically in the brain, the most severely affected organ in AGS. Although RNase H2
mice lacked the nuclease in astrocytes and a majority of neurons, no disease signs were apparent in these animals. We additionally confirmed these results in a second, neuron-specific RNase H2 knockout mouse line. However, when astrocytes were isolated from brains of RNase H2
mice and cultured under mitogenic conditions, they showed signs of DNA damage and premature senescence. Enhanced expression of interferon-stimulated genes (ISGs) represents the most reliable AGS biomarker. Importantly, primary RNase H2
astrocytes displayed significantly increased ISG transcript levels, which we failed to detect in
in brains of RNase H2
mice. Isolated astrocytes primed by DNA damage, including RNase H2-deficiency, exhibited a heightened innate immune response when exposed to bacterial or viral antigens. Taken together, we established a valid cellular AGS model that utilizes the very cell type responsible for disease pathology, the astrocyte, and phenocopies major molecular defects observed in AGS patient cells.
The putative protein tyrosine kinase (PTK) inhibitor tyrphostin AG126 has proven beneficial in various models of inflammatory disease. Yet molecular targets and cellular mechanisms remained ...enigmatic. We demonstrate here that AG126 treatment has beneficial effects in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. AG126 alleviates the clinical symptoms, diminishes encephalitogenic Th17 differentiation, reduces inflammatory CNS infiltration as well as microglia activation and attenuates myelin damage. We show that AG126 directly inhibits Bruton's tyrosine kinase (BTK), a PTK associated with B cell receptor and Toll‐like receptor (TLR) signaling. However, BTK inhibition cannot account for the entire activity spectrum. Effects on TLR‐induced proinflammatory cytokine expression in microglia involve AG126 hydrolysis and conversion of its dinitrile side chain to malononitrile (MN). Notably, while liberated MN can subsequently mediate critical AG126 features, full protection in EAE still requires delivery of intact AG126. Its anti‐inflammatory potential and especially interference with TLR signaling thus rely on a dual mechanism encompassing BTK and a novel MN‐sensitive target. Both principles bear great potential for the therapeutic management of disturbed innate and adaptive immune functions. GLIA 2015;63:1083–1099
Main Points
Tyrphostin AG126 has beneficial effects in mice with experimental autoimmune encephalomyelitis, by reducing inflammation and tissue damage.
AG126 directly inhibits Bruton's tyrosine kinase but also acts on a malononitrile‐sensitive target.
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