Interleukin 22 (IL-22), which is produced by cells of the T sub(H)17 subset of helper T cells and other leukocytes, not only enhances proinflammatory innate defense mechanisms in epithelial cells but ...also provides crucial protection to tissues from damage caused by inflammation and infection. In T sub(H)17 cells, transforming growth factor- beta (TGF- beta ) regulates IL-22 and IL-17 differently. IL-6 alone induces T cells to produce only IL-22, whereas the combination of IL-6 and high concentrations of TGF- beta results in the production of IL-17 but not IL-22 by T cells. Here we identify the transcription factor c-Maf, which is induced by TGF- beta , as a downstream repressor of Il22. We found that c-Maf bound to the Il22 promoter and was both necessary and sufficient for the TGF- beta -dependent suppression of IL-22 production in T sub(H)17 cells.
Abstract
Histamine H1 receptor (H1R) signaling in T cells plays an important role Th1 effector functions. H1R is an autoimmune susceptibility gene controlling experimental autoimmune ...encephalomyelitis (EAE). H1R knockout (H1RKO) mice also develop significantly less severe EAE compared to C57BL/6J wild-type mice in association with immune deviation of the CD4+ T-cell response from a Th1- to a Th2-like response. Little is known about the role of direct H1R signaling in the regulation of T-cell effector responses. In this study, T-cells from C57BL/6J and H1RKO mice were used to study H1R signaling in directly regulating such responses. Attempts to restore IFN-gammaproduction in H1RKO T-cells following retroviral transduction of the H1R were unsuccessful. In contrast, H1RKO transgenic mice selectively expressing the H1R in peripheral CD4+ T-cells under the control of the distal-lck promoter restored the IFN-gamma response and susceptibility to EAE in an H1R gene dose-dependent fashion. Moreover, activated H1RKO CD4+ T-cells show reduced phosphorylation of p38 MAP kinase compared to T-cells from wild-type mice which was again restored in activated T-cells from transgenic mice. These results show that H1R signaling regulates IFN-gamma production in CD4+ effector T-cells by direct signaling during initial activation of naïve T-cells through phosphorylation of p38 MAP kinase.
► The histamine H1 receptor (Hrh1/H1R) is a shared autoimmune disease gene. ► We selectively re-expressed H1R in CD11b+ myeloid cells of H1RKO mice. ► H1R re-expression by H1RKO-CD11b+ cells does not ...complement EAE susceptibility. ► H1R re-expression by H1RKO-CD11b+ cells does not affect T cell cytokine responses. ► Our results highlight the cell-specific effects of H1R in the pathogenesis of complex diseases such as EAE and MS.
The histamine H1 receptor (Hrh1/H1R) was identified as an autoimmune disease gene in experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis (MS). Previously, we showed that selective re-expression of H1R by endothelial cells or T cells in H1RKO mice significantly reduced or complemented EAE severity and cytokine responses, respectively. H1R regulates innate immune cells, which in turn influences peripheral and central nervous system CD4+ T cell effector responses. Therefore, we selectively re-expressed H1R in CD11b+ cells of H1RKO mice to test the hypothesis that H1R signaling in these cells contributes to EAE susceptibility. We demonstrate that transgenic re-expression of H1R by H1RKO-CD11b+ cells neither complements EAE susceptibility nor T cell cytokine responses highlighting the cell-specific effects of Hrh1 in the pathogenesis of EAE and MS, and the need for cell-specific targeting in optimizing therapeutic interventions based on such genes.
Histamine H.sub.3 receptor (Hrh3/H.sub.3 R) is primarily expressed by neurons in the central nervous system (CNS) where it functions as a presynaptic inhibitory autoreceptor and heteroreceptor. ...Previously, we identified an H.sub.3 R-mediated central component in susceptibility to experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis (MS), related to neurogenic control of blood brain barrier permeability and peripheral T cell effector responses. Furthermore, we identified Hrh3 as a positional candidate for the EAE susceptibility locus Eae8. Here, we characterize Hrh3 polymorphisms between EAE-susceptible and resistant SJL and B10.S mice, respectively, and show that Hrh3 isoform expression in the CNS is differentially regulated by acute peripheral inflammatory stimuli in an allele-specific fashion. Next, we show that Hrh3 is not expressed in any subpopulations of the immune compartment, and that secondary lymphoid tissue is anatomically poised to be regulated by central H.sub.3 R signaling. Accordingly, using transcriptome analysis, we show that, inflammatory stimuli elicit unique transcriptional profiles in the lymph nodes of H.sub.3 RKO mice compared to WT mice, which is indicative of negative regulation of peripheral immune responses by central H.sub.3 R signaling. These results further support a functional link between the neurogenic control of T cell responses and susceptibility to CNS autoimmune disease coincident with acute and/or chronic peripheral inflammation. Pharmacological targeting of H.sub.3 R may therefore be useful in preventing the development and formation of new lesions in MS, thereby limiting disease progression.
Abstract
Multiple sclerosis (MS) is an autoimmune disease characterized by progressive demyelination of the central nervous system (CNS). Therapies with limited efficacy are currently available for ...MS. The presence of autoreactive CD4 T helper (Th)1 and Th17 cells in the CNS is thought to be important for MS pathogenesis. Here, we show that pharmacological inhibition of p38 MAP kinase (MAPK) by SB203580 (SB) significantly ameliorates clinical EAE elicited by immunization of C57BL/6J mice with MOG35-45 (chronic EAE) and SJL/J mice with PLP135-151 (remitting-relapsing EAE). While SB treatment of actively immunized animals did not prevent immune infiltration of the CNS, it reduced production of IL-17, but not IFNγ by antigen-specific Th cells. Interestingly, when EAE was induced by passive transfer of encephalitogenic Th1-polarized cells, administration of SB to recipients also resulted in prevention of disease, along with reduced CNS infiltration and antigen-specific IFNγ and IL-17 production. Importantly, we show that genetic manipulation of p38 MAPK activity specifically in T cells was sufficient to alter EAE progression and IL-17 production. Taken together, our results indicate that p38 MAPK activation in Th1 and Th17 cells controls their pathogenic functions in autoimmune inflammatory disease of the CNS, suggesting that pharmacological targeting of components of this pathway specifically in T cells may be useful in the treatment of MS.
Abstract
Histamine (HA) is a key regulator of experimental allergic encephalomyelitis (EAE), the autoimmune disease model of multiple sclerosis (MS). Histidine decarboxylase deficient mice (HDCKO), ...which are unable to synthesize HA, exhibit more severe EAE and increased IFN-γ production by splenocytes in response to MOG35-55. HA exerts its effects through four different G protein coupled receptors (GPCR): H1, H2, H3 and H4 (H1-4R). Each HA-receptor has been shown to influence EAE pathogenesis. In the mammalian brain there is, however, evidence for the existence of non-GPCR signaling by HA which is picrotoxin-sensitive and mediated by chloride conductance. GABAA receptor subunits can form HA-gated chloride channels in vitro suggesting that an ionotropic HA-receptor might contain known ligand-gated chloride channel subunits. To test the hypothesis that non-GPCR signaling by HA plays a role in immune responses, we generated H1-4RKO mice and studied their susceptibility to EAE. Here we report that in contrast to HDCKO mice, H1-4RKO mice develop less severe EAE compared to WT animals. Furthermore, splenocytes from immunized H1-4RKO mice produce significantly less IFN-γ compared to WT mice. Taken together these data support the existence of a novel HA signaling pathway in regulating EAE susceptibility.
Histamine (HA) is a biogenic amine that mediates multiple physiological processes including immunomodulatory effects in allergic and inflammatory reactions, and also plays a key regulatory role in ...experimental allergic encephalomyelitis (EAE), the autoimmune model of multiple sclerosis (MS). The pleiotropic effects of HA are mediated by four G protein-coupled receptors:
Hrh1
/H
1
R,
Hrh2
/H
2
R,
Hrh3
/H
3
R, and
Hrh4
/H
4
R. H
4
R expression is primarily restricted to hematopoietic cells, and its role in autoimmune inflammatory demyelinating disease of the CNS has not been studied. In this report we show that, compared to wild type (WT) mice, animals with a disrupted
Hrh4
(H
4
RKO) develop more severe myelin oligodendrocyte glycoprotein 35–55 (MOG
35-55
) peptide-induced EAE. Mechanistically, we also show that H
4
R plays a role in determining the frequency of T regulatory (T
R
) cells in secondary lymphoid tissues, and regulates T
R
cell chemotaxis and suppressor activity. Moreover, the lack of H
4
R leads to an impairment of an anti-inflammatory response due to fewer T
R
cells in the CNS during the acute phase of the disease and an increase in the proportion of Th17 cells.
Abstract only
Multiple sclerosis (MS), and its mouse model EAE, are autoimmune (AI) diseases that depend on both genetic and environmental factors. Shared immunopathology genes, e.g.,
tyrosine ...kinase‐2
(
Tyk2
), may also be shared AI disease genes. DI mice have a single 2538 G → A missense mutation in
tyk2
making them AI arthritis resistant and
T. gondii
susceptible, unlike the wild‐type B10.Q/Ai (Ai) substrain. We induced EAE in DI and Ai mice with MOG
79‐96
‐CFA using a double injection protocol (2×). DI mice were resistant (0/46) to EAE while Ai (32/36) and F1 hybrids (43/50) were susceptible (p < 0.0001). Antigen specific production of RANTES and IFN‐γ were specifically increased in Ai and F1 mice. Thus,
tyk2
is a shared AI susceptibility gene, and EAE can be complemented genetically by one wild‐type
Tyk2
allele. Next, we tested whether EAE in DI mice could be complemented by environmental factors using MOG
79‐96
‐CFA + pertussis toxin (1× + PTX). DI mice immunized with 1× + PTX were significantly more susceptible to EAE than 2× immunized mice (33/36 vs. 0/46; p < 0.0001). Only RANTES changed significantly with both genetic and PTX complementation. In summary,
tyk2
is both a shared immunopathology and AI disease susceptibility allele that can be complemented both genetically and environmentally. Such SNPs are of considerable significance given the potential role of gene‐by‐environment interaction in MS susceptibility.
Research supported by NIH/NINDS R01 NS36526, R01 AI058052, R01 AI41747, P01AI45666‐08P4, and National Multiple Sclerosis Society RG3575A5
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