Publications

STAT3 is a Critical Regulator of Astrogliosis and Scar Formation after Spinal Cord Injury

Signaling mechanisms that regulate astrocyte reactivity and scar formation after spinal cord injury (SCI) are not well defined. We used the Cre recombinase (Cre)-loxP system under regulation of the mouse glial fibrillary acidic protein (GFAP) promoter to conditionally delete the cytokine and growth factor signal transducer, signal transducer and activator of transcription 3 (STAT3), from astrocytes. After SCI in GFAP-Cre reporter mice, >99% of spinal cord cells that exhibited Cre activity as detected by reporter protein expression were GFAP-expressing astrocytes. Conditional deletion (or knock-out) of STAT3 (STAT3-CKO) from astrocytes in GFAP-Cre-loxP mice was confirmed in vivo and in vitro. In uninjured adult STAT3-CKO mice, astrocytes appeared morphologically similar to those in STAT3+/+ mice except for a partially reduced expression of GFAP. In STAT3+/+ mice, phosphorylated STAT3 (pSTAT3) was not detectable in astrocytes in uninjured spinal cord, and pSTAT3 was markedly upregulated after SCI in astrocytes and other cell types near the injury. Mice with STAT3-CKO from astrocytes exhibited attenuated upregulation of GFAP, failure of astrocyte hypertrophy, and pronounced disruption of astroglial scar formation after SCI. These changes were associated with increased spread of inflammation, increased lesion volume and partially attenuated motor recovery over the first 28 d after SCI. These findings indicate that STAT3 signaling is a critical regulator of certain aspects of reactive astrogliosis and provide additional evidence that scar-forming astrocytes restrict the spread of inflammatory cells after SCI.

Reduced prepulse inhibition of startle in STAT6-deficient mice.

To determine the role of STAT6 transcription factors in brain function, we performed a battery of mouse behavioral analyses of STAT6-deficient mice. We recently showed that STAT6-deficient mice displayed increased locomotor activities and had reduced levels of dopamine transporter (DAT) expression in the striatum. To further examine the behavioral effects of STAT6 deficiency, we subjected STAT6-deficient mice to behavior task testing prepulse inhibition (PPI) of the auditory startle response. In acoustic prepulse conditions, STAT6-deficient mice displayed significantly lower levels of PPI in acoustic startle than did wild-type mice, indicating their sensorimotor gating deficits. Thus, STAT6 transcription factors may be crucially implicated in sensorimotor gating by modulating the expression of several genes, including DAT in brain neurons.

Radioresistant cells expressing TLR5 control the respiratory epithelium's innate immune responses to flagellin

Bacterial products (such as endotoxins and flagellin) trigger innate immune responses through TLRs. Flagellin-induced signalling involves TLR5 and MyD88 and, according to some reports, TLR4. Whereas epithelial and dendritic cells are stimulated by flagellin in vitro, the cell contribution to the in vivo response is still unclear. Here, we studied the respective roles of radioresistant and radiosensitive cells in flagellin-induced airway inflammation in mice. We found that i.n. delivery of flagellin elicits a transient change in respiratory function and an acute, pro-inflammatory response in the lungs, characterized by TLR5- and MyD88-dependent chemokine secretion and neutrophil recruitment. In contrast, TLR4, CD14 and TRIF were not essential for flagellin-mediated responses, indicating that TLR4 does not cooperate with TLR5 in the lungs. Respiratory function, chemokine secretion and airway infiltration by neutrophils were dependent on radioresistant, TLR5-expressing cells. Furthermore, lung haematopoietic cells also responded to flagellin by activating TNF-alpha production. We suggest that the radioresistant lung epithelial cells are essential for initiating early, TLR5-dependent signalling in response to flagellin and thus triggering the lung's innate immune responses.

Cytokine-Induced Injury of the Lacrimal and Salivary Glands

Damages to the lacrimal and salivary glands that accompany various autoimmune diseases are categorized as secondary Sjögren syndrome. Cytokines and free radicals are thought to be responsible for the pathologic changes, but the precise mechanisms are not clear. We evaluated whether cytokines alone can cause the damages in these exocrine tissues, and whether gaseous molecules such as nitric oxide (NO) play a role in these injuries. Various knockout (KO) mice as well as wild-type mice were injected intraperitoneally (i.p.) with the proinflammatory cytokines, IL-12 and IL-18, singly or in combination. Concurrent administration of IL-12 and IL-18 to mice caused serious atrophy in the lacrimal and salivary glands, which was spared when each cytokine was singly administered. Microscopically, there were apparently no infiltrating cells; nonetheless, numerous apoptotic cells were observed in the epithelium, which was confirmed by DNA ladder formation on gel electrophoresis. Serum levels of IFN-gamma and NO2/NO3 were markedly elevated. Combined injections of IL-12 and IL-18 caused the same changes in Fas-deficient and Fas-ligand deficient mice, as well as in perforin-KO mice, but the same changes were not detected in inducible NO synthase-KO mice or IFN-gamma KO mice. Thus, the synergistic effect of IL-12 and IL-18 was dependent on production of IFN-gamma and NO, but independent of Fas/Fas ligand system and perforin-dependent cytotoxic T cells. IL-18 together with IL-12 caused destructive changes in the glandular tissues without apparent lymphocyte infiltration. It is suggested that these cytokines can mediate apoptosis in glandular epithelial cells and that the elevated NO production is responsible for the change.

Faculty Opinions recommendation of Endosomes are specialized platforms for bacterial sensing and NOD2 signalling.

TRAF6 Is Required for Generation of the B-1a B Cell Compartment as well as T Cell-Dependent and -Independent Humoral Immune Responses

TNF receptor superfamily members, such as CD40 and the Toll-like receptors (TLRs), regulate many aspects of B cell differentiation and activation. TRAF6 is an intracellular signaling adaptor molecule for these receptors, but its role in B cells has not been clarified by previous genetic approaches, as the systemic deletion of the TRAF6 gene results in perinatal lethality. Here we show that B cell-specific TRAF6 deficiency results in a reduced number of mature B cells in the bone marrow and spleen. Optimal T cell-dependent (TD) antigen responses, as characterized by isotype switching and long-lived plasma cell generation, are also impaired in B cell-specific TRAF6-deficient mice. B cell-specific TRAF6-deficient mice also exhibit lower levels of serum IgM and IgG2b and defective antigen-specific IgM production in response to T cell-independent (TI) antigens. Unexpectedly, TRAF6-deficient B cell progenitors are unable to generate CD5(+) B-1 cells. These results reveal critical roles for TRAF6 in TD and TI humoral immune responses and in inductive fate decisions necessary to generate the B-1 B cell compartment.

Molecular mechanisms of somatic dna recombination in antigen receptor genes

IL-18 deficiency selectively enhances allergen-induced eosinophilia in mice

Background: TH2 cytokines are associated with airway inflammation and hyperreactivity in bronchial asthma, and restoration of the TH1/TH2 imbalance is a potential avenue for novel therapies. IL-18 is a cytokine secreted by activated macrophages, and it shares some of its biologic activities with IL-12, a typical TH1-type cytokine. Although IL-18 and IL-12 act on T cells synergistically to induce IFN-γ production, the contribution of IL-18 TH1/TH2 imbalance and to subsequent asthmatic response has not been elucidated in vivo. Objective: We studied a model of allergic asthma in IL-18–deficient mice to investigate the modulatory role of IL-18 on induction and maintenance of TH2 mucosal immunity. We also have investigated the ability of intraperitoneal instilled IL-18 to reduce TH2 mucosal immunity in IL-18–deficient mice. Methods: IL-18–deficient mice immunized to ovalbumin by means of intraperitoneal injection were challenged 3 times with an aerosol of ovalbumin every second day for 8 days. Recombinant (r)IL-18 was intraperitoneally administered in mice before every first challenge. Mice were analyzed for effects on lung eosinophilia, cytokines, and serum IgE levels. Results: In IL-18–deficient mice, levels of eosinophilia and lung damage were significantly higher than in wild-type C57/BL6 litter mates. Intraperitoneal administration of rIL-18 in deficient mice reduced these antigen-induced changes to levels seen in wild-type mice in association with a decrease in IL-4 in bronchoalveolar lavage fluid and lung tissue. However, administration of rIL-18 did not affect the IFN-γ level and somewhat enhanced the production of IL-5. Notably, reconstitution with rIL-18 increased the numbers of cells staining for Fas ligand, as well as apoptotic cells stained by nick end-labeling in bronchial submucosa infiltrates. Conclusion: These findings indicate that in vivo IL-18 not only inhibited antigen-specific TH2 development but also affected apoptosis through Fas-Fas ligand interactions. These data support a role for IL-18 in the complex pathogenesis of allergic inflammation in which IL-18 limited the development of the local inflammatory response to antigen. (J Allergy Clin Immunol 2000;105:45-53.)

Essential Immunoregulatory Role for BCAP in B Cell Development and Function

BCAP was recently cloned as a binding molecule to phosphoinositide 3-kinase (PI3K). To investigate the role of BCAP, mutant mice deficient in BCAP were generated. While BCAP-deficient mice are viable, they have decreased numbers of mature B cells and B1 B cell deficiency. The mice produce lower titers of serum immunoglobulin (Ig)M and IgG3, and mount attenuated responses to T cell–independent type II antigen. Upon B cell receptor cross-linking, BCAP-deficient B cells exhibit reduced Ca2+ mobilization and poor proliferative responses. These findings demonstrate that BCAP plays a pivotal immunoregulatory role in B cell development and humoral immune responses.

Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway

No abstract is provided for this article.

Faculty Opinions recommendation of Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome.

Quantitative Proteomics Reveals Subset-Specific Viral Recognition in Dendritic Cells

Dendritic cell (DC) populations consist of multiple subsets that are essential orchestrators of the immune system. Technological limitations have so far prevented systems-wide accurate proteome comparison of rare cell populations in vivo. Here, we used high-resolution mass spectrometry-based proteomics, combined with label-free quantitation algorithms, to determine the proteome of mouse splenic conventional and plasmacytoid DC subsets to a depth of 5,780 and 6,664 proteins, respectively. We found mutually exclusive expression of pattern recognition pathways not previously known to be different among conventional DC subsets. Our experiments assigned key viral recognition functions to be exclusively expressed in CD4+ and double-negative DCs. The CD8α+ DCs largely lack the receptors required to sense certain viruses in the cytoplasm. By avoiding activation via cytoplasmic receptors, including retinoic acid-inducible gene I, CD8α+ DCs likely gain a window of opportunity to process and present viral antigens before activation-induced shutdown of antigen presentation pathways occurs.

Contributors

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Activation and regulation of Toll-like receptors 2 and 1 in human leprosy

No abstract is provided for this article.

X-ray crystal structure of IRF-3 and its functional implications

No abstract is provided for this article.

Immunoregulation in Urinary Tract Inflammation—A Role of Tamm-Horsfall Glycoprotein

The Tamm-Horsfall protein (THP), the most abundant protein in normal urine, was discovered five decades ago ([1][1]), or possibly even much earlier ([2][2]), but the role for the most abundant protein in normal urine had remained enigmatic for a long time. It is expressed in the thick ascending limb

Deletion of Tribbles Pseudokinase-3 Ameliorates Retinal Function in CEP290RD16 Mice

No abstract is provided for this article.

[Role of toll-like receptor in innate immunity].

No abstract is provided for this article.