Like other autoimmune diseases, rheumatoid arthritis (RA) develops in distinct stages, with each phase of disease linked to immune cell dysfunction. HLA class II genes confer the strongest genetic risk to develop RA. They encode for molecules essential in the activation and differentiation of T cells, placing T cells upstream in the immunopathology. In Phase 1 of the RA disease process, T cells lose a fundamental function, their ability to be self-tolerant, and provide help for autoantibody-producing B cells. Phase 2 begins many years later, when mis-differentiated T cells gain tissue-invasive effector functions, enter the joint, promote non-resolving inflammation, and give rise to clinically relevant arthritis. In Phase 3 of the RA disease process, abnormal innate immune functions are added to adaptive autoimmunity, converting synovial inflammation into a tissue-destructive process that erodes cartilage and bone. Emerging data have implicated metabolic mis-regulation as a fundamental pathogenic pathway in all phases of RA. Early in their life cycle, RA T cells fail to repair mitochondrial DNA, resulting in a malfunctioning metabolic machinery. Mitochondrial insufficiency is aggravated by the mis-trafficking of the energy sensor AMPK away from the lysosomal surface. The metabolic signature of RA T cells is characterized by the shunting of glucose toward the pentose phosphate pathway and toward biosynthetic activity. During the intermediate and terminal phase of RA-imposed tissue inflammation, tissue-residing macrophages, T cells, B cells and stromal cells are chronically activated and under high metabolic stress, creating a microenvironment poor in oxygen and glucose, but rich in metabolic intermediates, such as lactate. By sensing tissue lactate, synovial T cells lose their mobility and are trapped in the tissue niche. The linkage of defective DNA repair, misbalanced metabolic pathways, autoimmunity, and tissue inflammation in RA encourages metabolic interference as a novel treatment strategy during both the early stages of tolerance breakdown and the late stages of tissue inflammation. Defining and targeting metabolic abnormalities provides a new paradigm to treat, or even prevent, the cellular defects underlying autoimmune disease.

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The aorta and the large conductive arteries are immunoprivileged tissues and are protected against inflammatory attack. A breakdown of the immunoprivilege leads to autoimmune vasculitis, such as giant cell arteritis (GCA), in which CD8 + T regulatory (Treg) cells fail to contain CD4 + T cells and macrophages, resulting in the formation of tissuedestructive granulomatous lesions. Here, we report that the molecular defect of malfunctioning CD8 + Treg cells lies in aberrant NOTCH4 signaling that deviates endosomal trafficking and minimizes exosome production. By transcriptionally controlling the profile of RAB GTPases, NOTCH4 signaling restricted vesicular secretion of the enzyme NADPH oxidase 2 (NOX2). Specifically, NOTCH4 hi CD8 + Treg cells increased RAB5A and RAB11A expression and suppressed RAB7A, culminating in the accumulation of early and recycling endosomes and sequestering of NOX2 in an intracellular compartment. RAB7A lo CD8 + Treg cells failed in the surface translocation and the exosomal release of NOX2. NOTCH4 hi RAB5A hi RAB7A lo RAB11A hi CD8 + Treg cells left adaptive immunity unopposed, enabling a breakdown in tissue tolerance and aggressive vessel wall inflammation. Inhibiting NOTCH4 signaling corrected the defect and protected arteries from inflammatory insult. The study implicates NOTCH4dependent transcriptional control of RAB proteins and intracellular vesicle trafficking in autoimmune disease and in vascular inflammation.

Melatonin is a key hormone that regulates circadian rhythms, metabolism, and reproduction. However, the mechanisms of melatonin synthesis and secretion have not been fully defined. The purpose of this study was to investigate the functions of the LIM homeobox transcription factor Isl1 in regulating melatonin synthesis and secretion in porcine pineal gland. We found that Isl1 is highly expressed in the melatonin-producing cells in the porcine pineal gland. Further functional studies demonstrate that Isl1 knockdown in cultured primary porcine pinealocytes results in the decline of melatonin and arylalkylamine N-acetyltransferase (AANAT) mRNA levels by 29.2% and 72.2%, respectively, whereas Isl1 overexpression raised by 1.3-fold and 2.7-fold. In addition, the enhancing effect of norepinephrine (NE) on melatonin synthesis was abolished by Isl1 knockdown. The in vivo intracerebroventricular NE injections upregulate Isl1 mRNA and protein levels by about threefold and 4.5-fold in the porcine pineal gland. We then examined the changes in Isl1 expression in the pineal gland and global melatonin levels throughout the day. The results show that Isl1 protein level at 24:00 is 2.5-fold higher than that at 12:00, which is parallel to melatonin levels. We further found that Isl1 increases the activity of AANAT promoter, and the effect of NE on Isl1 expression was blocked by an ERK inhibitor. Collectively, the results presented here demonstrate that Isl1 positively modulates melatonin synthesis by targeting AANAT, via the ERK signaling pathway of NE. These suggest that Isl1 plays important roles in maintaining the daily circadian rhythm.