Axonal response of mitochondria to demyelination and complex IV activity within demyelinated axons in experimental models of multiple sclerosis.

Aims: Axonal injury in multiple sclerosis (MS) and experimental models is most frequently detected in acutely demyelinating lesions. We recently reported a compensatory neuronal response, where mitochondria move to the acutely demyelinated axon and increase the mitochondrial content following lysolecithin-induced demyelination. We termed this homeostatic phenomenon, which is also evident in MS, the axonal response of mitochondria to demyelination (ARMD).

Antigen receptor-engineered Tregs inhibit CNS autoimmunity in cell therapy using nonredundant immune mechanisms in mice.

CD4 FOXP3 Tregs are currently explored to develop cell therapies against immune-mediated disorders, with an increasing focus on antigen receptor-engineered Tregs. Deciphering their mode of action is necessary to identify the strengths and limits of this approach. Here, we addressed this issue in an autoimmune disease of the CNS, EAE.

Prostaglandin E promotes intestinal inflammation via inhibiting microbiota-dependent regulatory T cells.

The gut microbiota fundamentally regulates intestinal homeostasis and disease partially through mechanisms that involve modulation of regulatory T cells (T), yet how the microbiota-T cross-talk is physiologically controlled is incompletely defined. Here, we report that prostaglandin E (PGE), a well-known mediator of inflammation, inhibits mucosal T in a manner depending on the gut microbiota. PGE through its receptor EP4 diminishes T-favorable commensal microbiota.

The Helminth Parasite Attenuates EAE in an IL-4Rα-Dependent Manner.

Helminth parasites are effective in biasing Th2 immunity and inducing regulatory pathways that minimize excessive inflammation within their hosts, thus allowing chronic infection to occur whilst also suppressing bystander atopic or autoimmune diseases. Multiple sclerosis (MS) is a severe autoimmune disease characterized by inflammatory lesions within the central nervous system; there are very limited therapeutic options for the progressive forms of the disease and none are curative. Here, we used the experimental autoimmune encephalomyelitis (EAE) model to examine if the intestinal helminth and its excretory/secretory products (HES) are able to suppress inflammatory disease.

Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis.

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination.

Purine metabolism controls innate lymphoid cell function and protects against intestinal injury.

Inflammatory bowel disease (IBD) is a condition of chronic inflammatory intestinal disorder with increasing prevalence but limited effective therapies. The purine metabolic pathway is involved in various inflammatory processes including IBD. However, the mechanisms through which purine metabolism modulates IBD remain to be established.

Methyl donor deficient diets cause distinct alterations in lipid metabolism but are poorly representative of human NAFLD.

: Non-alcoholic fatty liver disease (NAFLD) is a global health issue. Dietary methyl donor restriction is used to induce a NAFLD/non-alcoholic steatohepatitis (NASH) phenotype in rodents, however the extent to which this model reflects human NAFLD remains incompletely understood. To address this, we undertook hepatic transcriptional profiling of methyl donor restricted rodents and compared these to published human NAFLD datasets.

Facilitation of IL-22 production from innate lymphoid cells by prostaglandin E prevents experimental lung neutrophilic inflammation.

Acute lung injury is a neutrophil-dominant, life-threatening disease without effective therapies and better understanding of the pathophysiological mechanisms involved is an urgent need. Here we show that interleukin (IL)-22 is produced from innate lymphoid cells (ILC) and is responsible for suppression of experimental lung neutrophilic inflammation. Blocking prostaglandin E (PGE) synthesis reduces lung ILCs and IL-22 production, resulting in exacerbation of lung neutrophilic inflammation.

A Context-Dependent Role for αv Integrins in Regulatory T Cell Accumulation at Sites of Inflammation.

Several inflammatory diseases including multiple sclerosis and inflammatory bowel disease have been associated with dysfunctional and/or reduced numbers of Foxp3 regulatory T cells (Treg). While numerous mechanisms of action have been discovered by which Treg can exert their function, disease-specific Treg requirements remain largely unknown. We found that the integrin αv, which can pair with several β subunits including β8, is highly upregulated in Treg at sites of inflammation.

The STAT3-IL-10-IL-6 Pathway Is a Novel Regulator of Macrophage Efferocytosis and Phenotypic Conversion in Sterile Liver Injury.

The disposal of apoptotic bodies by professional phagocytes is crucial to effective inflammation resolution. Our ability to improve the disposal of apoptotic bodies by professional phagocytes is impaired by a limited understanding of the molecular mechanisms that regulate the engulfment and digestion of the efferocytic cargo. Macrophages are professional phagocytes necessary for liver inflammation, fibrosis, and resolution, switching their phenotype from proinflammatory to restorative.

IL-33 and ST2 mediate FAK-dependent antitumor immune evasion through transcriptional networks.

Focal adhesion kinase (FAK) mediates tumor cell-intrinsic behaviors that promote tumor growth and metastasis. We previously showed that FAK also induces the expression of inflammatory genes that inhibit antitumor immunity in the microenvironment. We identified a crucial, previously unknown role for the dual-function cytokine interleukin-33 (IL-33) in FAK-dependent immune evasion.

A structurally distinct TGF-β mimic from an intestinal helminth parasite potently induces regulatory T cells.

Helminth parasites defy immune exclusion through sophisticated evasion mechanisms, including activation of host immunosuppressive regulatory T (Treg) cells. The mouse parasite Heligmosomoides polygyrus can expand the host Treg population by secreting products that activate TGF-β signalling, but the identity of the active molecule is unknown. Here we identify an H.

NKT cells are important mediators of hepatic ischemia-reperfusion injury.

Introduction: IRI results from the interruption then reinstatement of an organ's blood supply, and this poses a significant problem in liver transplantation and resectional surgery. In this paper, we explore the role T cells play in the pathogenesis of this injury.

Materials & Methods: We used an in vivo murine model of warm partial hepatic IRI, genetically-modified mice, in vivo antibody depletion, adoptive cell transfer and flow cytometry to determine which lymphocyte subsets contribute to pathology.

FAK-inhibition opens the door to checkpoint immunotherapy in Pancreatic Cancer.

Immunotherapy has had remarkable success in the treatment of some cancer types. However, pancreatic cancer has remained largely refractory to immunotherapy, including immune checkpoint inhibitors. Recently, Jiang and colleagues identified a key role for FAK in regulating the composition of the fibrotic and immuno-suppressive pancreatic tumour niche, and showed that FAK inhibitors can be used in combination with immune checkpoint blockade and gemcitabine chemotherapy to significantly delay pancreatic tumour progression.

IL-10-producing, ST2-expressing Foxp3 T cells in multiple sclerosis brain lesions.

CD4Foxp3 T regulatory (Treg) cells provide a key defence against inflammatory disease, but also have an ability to produce pro-inflammatory cytokines. The evidence for these two possibilities in multiple sclerosis (MS) is controversial. However, this has largely been based on studies of circulating Treg cells derived from peripheral blood, rather than the central nervous system.

Thymus-Derived Regulatory T Cells Are Positively Selected on Natural Self-Antigen through Cognate Interactions of High Functional Avidity.

Regulatory T (Treg) cells expressing Foxp3 transcripton factor are essential for immune homeostasis. They arise in the thymus as a separate lineage from conventional CD4(+)Foxp3(-) T (Tconv) cells. Here, we show that the thymic development of Treg cells depends on the expression of their endogenous cognate self-antigen.

Prostaglandin E₂ constrains systemic inflammation through an innate lymphoid cell-IL-22 axis.

Systemic inflammation, which results from the massive release of proinflammatory molecules into the circulatory system, is a major risk factor for severe illness, but the precise mechanisms underlying its control are not fully understood. We observed that prostaglandin E2 (PGE2), through its receptor EP4, is down-regulated in human systemic inflammatory disease. Mice with reduced PGE2 synthesis develop systemic inflammation, associated with translocation of gut bacteria, which can be prevented by treatment with EP4 agonists.

Eliminating roles for T-bet and IL-2 but revealing superior activation and proliferation as mechanisms underpinning dominance of regulatory T cells in tumors.

Foxp3(+) regulatory T cells (Tregs) are often highly enriched within the tumor-infiltrating T cell pool. Using a well-characterised model of carcinogen-induced fibrosarcomas we show that the enriched tumor-infiltrating Treg population comprises largely of CXCR3(+) T-bet(+) 'TH1-like' Tregs which are thymus-derived Helios(+) cells. Whilst IL-2 maintains homeostatic ratios of Tregs in lymphoid organs, we found that the perturbation in Treg frequencies in tumors is IL-2 independent.

Acute Liver Injury Is Independent of B Cells or Immunoglobulin M.

Background & Aims: Acute liver injury is a clinically important pathology and results in the release of Danger Associated Molecular Patterns, which initiate an immune response. Withdrawal of the injurious agent and curtailing any pathogenic secondary immune response may allow spontaneous resolution of injury. The role B cells and Immunoglobulin M (IgM) play in acute liver injury is largely unknown and it was proposed that B cells and/or IgM would play a significant role in its pathogenesis.

Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity.

Focal adhesion kinase (FAK) promotes anti-tumor immune evasion. Specifically, the kinase activity of nuclear-targeted FAK in squamous cell carcinoma (SCC) cells drives exhaustion of CD8(+) T cells and recruitment of regulatory T cells (Tregs) in the tumor microenvironment by regulating chemokine/cytokine and ligand-receptor networks, including via transcription of Ccl5, which is crucial. These changes inhibit antigen-primed cytotoxic CD8(+) T cell activity, permitting growth of FAK-expressing tumors.

Inflammation-associated genes: risks and benefits to Foxp3+ regulatory T-cell function.

Foxp3(+) regulatory T (Treg) cells prevent the development of autoimmunity and immunopathology, as well as maintaining homeostasis and tolerance to commensal microorganisms. The suppressive activity of Treg cells is their defining characteristic, generating great interest in their therapeutic potential. However, suppressive and effector functions are not entirely exclusive.