Ulcerative colitis (UC) is linked with inflammation of the large intestine due to an overactive response of the colon-immune system. UC is associated with weight loss, rectal bleeding, diarrhea, and ...abdominal pain. Given that γ-amino butyric acid (GABA) suppresses immune cell activity and the excitability of colonic afferents, and that there is a decrease in colonic GABA during UC, we hypothesized that UC pain is due to a decrease in the inhibition of colonic afferents. Thus, restoring GABA in the colon will attenuate inflammatory hypersensitivity. We tested this hypothesis in a mouse model of colitis. Colon inflammation was induced with seven days of dextran sodium sulfate (DSS, 3%) in the drinking water. GABA (40 mg/kg) was administered orally for the same period as DSS, and body weight, colon length, colon permeability, clinical progression of colitis (disease activity index or DAI), and colon histological score (HS) were assessed to determine the effects of GABA on colitis. A day after the end of GABA treatment, visceral sensitivity was assessed with balloon distention (of the colon)-evoked visceromotor response and colon samples were collected for the measurement of GABA and cytokines. Treatment with GABA reduced the DSS-induced increase in the colon permeability, DAI, HS, and decrease in body weight and colon length. Furthermore, GABA inhibited the DSS-induced increase in the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-12 (IL-12), and increased the expression of the anti-inflammatory cytokine IL-10 in the colon tissue. Importantly, GABA reduced DSS-induced visceral hypersensitivity. These data suggest that increasing gastrointestinal levels of GABA may be useful for the treatment of colitis.
GABA treatment reduces the severity of colitis and inflammation and produces inhibition of visceral hypersensitivity in colon-inflamed mice. These results raise the promising possibility that GABA treatment may be an effective therapeutic strategy for the management of symptoms associated with colitis. However, clinical studies are required to corroborate whether this mouse-model data translates to human colon.
To investigate which cytokines, chemokines and growth factors are involved in the immunopathogenesis of idiopathic uveitis, and whether cytokine profiles are associated with. Serum and aqueous humor ...(AH) samples of 75 patients with idiopathic uveitis were analyzed by multiplex immunoassay. Infectious controls consisted of 16 patients with ocular toxoplasmosis all confirmed by intraocular fluid analyses. Noninfectious controls consisted of 7 patients with Behçet disease related uveitis and 15 patients with sarcoidosis related uveitis. The control group consisted of AH and serum samples from 47 noninflammatory control patients with age-related cataract. In each sample, 27 immune mediators ± IL-21 and IL-23 were measured. In idiopathic uveitis, 13 of the 29 mediators, including most proinflammatory and vascular mediators such as IL-6, IL-8, IL-12, G-CSF, GM-CSF, MCP-1, IP-10, TNF-α and VEGF, were significantly elevated in the aqueous humor when compared to all controls. Moreover, IL-17, IP-10, and IL-21, were significantly elevated in the serum when compared to all controls. We clustered 4 subgroups of idiopathic uveitis using a statistical analysis of hierarchical unsupervised classification, characterized by the order of magnitude of concentrations of intraocular cytokines. The pathogenesis of idiopathic uveitis is characterized by the presence of predominantly proinflammatory cytokines and chemokines and vascular endothelial growth factor with high expression levels as compared to other causes of uveitis. There are indications for obvious Th-1/ IL21-Th17 pathways but also IL9-Th9 and increased IFN-γ-inducing cytokine (IL12) and IFN-γ-inducible CXC chemokine (IP-10). The combined data suggest that immune mediator expression is different among idiopathic uveitis. This study suggests various clusters among the idiopathic uveitis group rather than one specific uveitis entity.
Despite widespread acceptance that neuroinflammation contributes to age-related cognitive decline, studies comparing protein expression of cytokines in the young versus old brains are surprisingly ...limited in terms of the number of cytokines and brain regions studied. Complicating matters, discrepancies abound-particularly for interleukin 6 (IL-6)-possibly due to differences in sex, species/strain, and/or the brain regions studied.
As such, we clarified how cytokine expression changes with age by using a Bioplex and Western blot to measure multiple cytokines across several brain regions of both sexes, using 2 mouse strains bred in-house as well as rats obtained from NIA. Parametric and nonparametric statistical tests were used as appropriate.
In the ventral hippocampus of C57BL/6J mice, we found age-related increases in IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-6, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-17, eotaxin, G-CSF, interfeuron δ, KC, MIP-1a, MIP-1b, rantes, and TNFα that are generally more pronounced in females, but no age-related change in IL-5, MCP-1, or GM-CSF. We also find aging is uniquely associated with the emergence of a module (a.k.a. network) of 11 strongly intercorrelated cytokines, as well as an age-related shift from glycosylated to unglycosylated isoforms of IL-10 and IL-1β in the ventral hippocampus. Interestingly, age-related increases in extra-hippocampal cytokine expression are more discreet, with the prefrontal cortex, striatum, and cerebellum of male and female C57BL/6J mice demonstrating robust age-related increase in IL-6 expression but not IL-1β. Importantly, we found this widespread age-related increase in IL-6 also occurs in BALB/cJ mice and Brown Norway rats, demonstrating conservation across species and rearing environments.
Thus, age-related increases in cytokines are more pronounced in the hippocampus compared to other brain regions and can be more pronounced in females versus males depending on the brain region, genetic background, and cytokine examined.
The amino acid and oligopeptide transporter Solute carrier family 15 member A4 (SLC15A4), which resides in lysosomes and is preferentially expressed in immune cells, plays critical roles in the ...pathogenesis of lupus and colitis in murine models. Toll-like receptor (TLR)7/9- and nucleotide-binding oligomerization domain-containing protein 1 (NOD1)-mediated inflammatory responses require SLC15A4 function for regulating the mechanistic target of rapamycin complex 1 (mTORC1) or transporting L-Ala-γ-D-Glu-meso-diaminopimelic acid, IL-12: interleukin-12 (Tri-DAP), respectively. Here, we further investigated the mechanism of how SLC15A4 directs inflammatory responses. Proximity-dependent biotin identification revealed glycolysis as highly enriched gene ontology terms. Fluxome analyses in macrophages indicated that SLC15A4 loss causes insufficient biotransformation of pyruvate to the tricarboxylic acid cycle, while increasing glutaminolysis to the cycle. Furthermore, SLC15A4 was required for M1-prone metabolic change and inflammatory IL-12 cytokine productions after TLR9 stimulation. SLC15A4 could be in close proximity to AMP-activated protein kinase (AMPK) and mTOR, and SLC15A4 deficiency impaired TLR-mediated AMPK activation. Interestingly, SLC15A4-intact but not SLC15A4-deficient macrophages became resistant to fluctuations in environmental nutrient levels by limiting the use of the glutamine source; thus, SLC15A4 was critical for macrophage's respiratory homeostasis. Our findings reveal a mechanism of metabolic regulation in which an amino acid transporter acts as a gatekeeper that protects immune cells' ability to acquire an M1-prone metabolic phenotype in inflammatory tissues by mitigating metabolic stress.
Immunomodulation involves two mechanisms, immunostimulation and immunosuppression. It is a complex mechanism that regulates the pathophysiology and pathogenesis of various diseases affecting the ...immune system. Immunomodulators can be used as immunostimulators to reduce the side effects of drugs that induce immunosuppression. In this study, we characterized the chemical composition of high molecular weight fucoidan (HMWF) and low molecular weight fucoidan and compared their functions as natural killer (NK) cell-derived immunostimulators in vitro. We also tested the effectiveness of HMWF, which has a relatively high function in vitro, as an immunostimulator in immunosuppressed animal models. In these models, HWMF significantly restored NK cell cytotoxicity and granzyme B release to the control group level. In addition, the expression of interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-12, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α also increased in the spleen. This study suggests that HMWF acts as an effective immunostimulant under immunosuppressive conditions.
Oocyte development and fertilization are largely influenced by the microenvironment of the follicular fluid (FF), and the exploration of its molecular/metabolic composition may help in improving in ...vitro fertilization (IVF) outcomes. Here, the concentrations of molecules related to oxidative stress/inflammation were measured in FF from follicles at oocyte retrieval during IVF. Here, the FF antioxidant potential was correlated with the number of retrieved/mature oocytes and the number of fertilized ones. FF collected from the follicles of normal fertilized oocytes presented an elevated antioxidant capability, lower levels of pro-inflammatory molecules (i.e., IL-6, IL-8, IL-12, TGF-β, and HIF-1α), and a higher IL-10 concentration. FF samples from follicles at oocyte retrieval that resulted in top-quality embryos displayed a peculiar antioxidant capability and a further decrease in proinflammatory molecules when compared with FF, giving rise to poor-quality embryos. Finally, pro-inflammatory molecules were lower and accompanied by a high antioxidant capability in samples giving rise to successful embryo implantation. The antioxidant capability and IL-10 displayed a good predictive ability for fertilization and embryo quality. Overall, our data showed the great influence of oxidative stress on the oocytes’ fertilization, and shed light on the importance of controlling the inflammatory and oxidative status of FF to obtain good-quality embryos with significant implantation potential.
Newborns are highly susceptible to infection. The underlying mechanism of neonatal infection susceptibility has generally been associated with neonatal immune cell immaturity. In this study, we ...challenged this notion and built upon our recent discovery that neonates are physiologically enriched with erythroid TER119
CD71
cells (Elahi et al. 2013.
504: 158-162). We have used
, a common neonatal respiratory tract infection, as a proof of concept to investigate the role of these cells in newborns. We found that CD71
cells have distinctive immune-suppressive properties and suppress innate immune responses against
infection. CD71
cell ablation unleashed innate immune response and restored resistance to
infection. In contrast, adoptive transfer of neonatal CD71
cells into adult recipients impaired their innate immune response to
infection. Enhanced innate immune response to
was characterized by increased production of protective cytokines IFN-γ, TNF-α, and IL-12, as well as recruitment of NK cells, CD11b
, and CD11c
cells in the lung. Neonatal and human cord blood CD71
cells express arginase II, and this enzymatic activity inhibits phagocytosis of
in vitro. Thus, our study challenges the notion that neonatal infection susceptibility is due to immune cell-intrinsic defects and instead highlights active immune suppression mediated by abundant CD71
cells in the newborn. Our findings provide additional support for the novel theme in neonatal immunology that immunosuppression is essential to dampen robust immune responses in the neonate. We anticipate that our results will spark renewed investigation in modulating the function of these cells and developing novel strategies for enhancing host defense to infections in newborns.
Purpose
Hyper activation of the JAK-STAT signaling underlies the pathophysiology of many human immune–mediated diseases. Herein, the study of 2 adult patients with SOCS1 haploinsufficiency ...illustrates the severe and pleomorphic consequences of its impaired regulation in the intestinal tract.
Methods
Two unrelated adult patients presented with gastrointestinal manifestations, one with Crohn’s disease-like ileo-colic inflammation refractory to anti-TNF and the other with lymphocytic leiomyositis causing severe chronic intestinal pseudo-occlusion. Next-generation sequencing was used to identify the underlying monogenic defect. One patient received anti-IL-12/IL-23 treatment while the other received the JAK1 inhibitor, ruxolitinib. Peripheral blood, intestinal tissues, and serum samples were analyzed before-and-after JAK1 inhibitor therapy using mass cytometry, histology, transcriptomic, and Olink assay.
Results
Novel germline loss-of-function variants in
SOCS1
were identified in both patients. The patient with Crohn-like disease achieved clinical remission with anti-IL-12/IL-23 treatment. In the second patient with lymphocytic leiomyositis, ruxolitinib induced rapid resolution of the obstructive symptoms, significant decrease of the CD8+ T lymphocyte muscular infiltrate, and normalization of serum and intestinal cytokines. Decreased frequencies of circulating Treg cells, MAIT cells, and NK cells, with altered CD56
bright
:CD16
lo
:CD16
hi
NK subtype ratios were not modified by ruxolitinib.
Conclusion
SOCS1 haploinsufficiency can result in a broad spectrum of intestinal manifestations and need to be considered as differential diagnosis in cases of severe treatment-refractory enteropathies, including the rare condition of lymphocytic leiomyositis. This provides the rationale for genetic screening and considering JAK inhibitors in such cases.
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