STAT3 signaling in myeloid cells promotes pathogenic myelin-specific T cell differentiation and autoimmune demyelination.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system. Dysregulation of STAT3, a transcription factor pivotal to various cellular processes including Th17 cell differentiation, has been implicated in MS. Here, we report that STAT3 is activated in infiltrating monocytic cells near active MS lesions and that activation of STAT3 in myeloid cells is essential for leukocyte infiltration, neuroinflammation, and demyelination in experimental autoimmune encephalomyelitis (EAE). Genetic disruption of Stat3 in peripheral myeloid lineage cells abrogated EAE, which was associated with decreased antigen-specific T helper cell responses. Myeloid cells from immunized Stat3 mutant mice exhibited impaired antigen-presenting functions and were ineffective in driving encephalitogenic T cell differentiation. Single-cell transcriptome analyses of myeloid lineage cells from preclinical wild-type and mutant mice revealed that loss of myeloid STAT3 signaling disrupted antigen-dependent cross-activation of myeloid cells and T helper cells. This study identifies a previously unrecognized requisite for myeloid cell STAT3 in the activation of myelin-reactive T cells and suggests myeloid STAT3 as a potential therapeutic target for autoimmune demyelinating disease.

Brain region dependent molecular signatures and myelin repair following chronic demyelination.

Multiple sclerosis (MS) is the most prevalent demyelinating disease of the central nervous system, characterized by myelin destruction, axonal degeneration, and progressive loss of neurological functions. Remyelination is considered an axonal protection strategy and may enable functional recovery, but the mechanisms of myelin repair, especially after chronic demyelination, remain poorly understood. Here, we used the cuprizone demyelination mouse model to investigate spatiotemporal characteristics of acute and chronic de- and remyelination and motor functional recovery following chronic demyelination. Extensive remyelination occurred after both the acute and chronic insults, but with less robust glial responses and slower myelin recovery in the chronic phase. Axonal damage was found at the ultrastructural level in the chronically demyelinated corpus callosum and in remyelinated axons in the somatosensory cortex. Unexpectedly, we observed the development of functional motor deficits after chronic remyelination. RNA sequencing of isolated brain regions revealed significantly altered transcripts across the corpus callosum, cortex and hippocampus. Pathway analysis identified selective upregulation of extracellular matrix/collagen pathways and synaptic signaling in the chronically de/remyelinating white matter. Our study demonstrates regional differences of intrinsic reparative mechanisms after a chronic demyelinating insult and suggests a potential link between long-term motor function alterations and continued axonal damage during chronic remyelination. Moreover, the transcriptome dataset of three brain regions and over an extended de/remyelination period provides a valuable platform for a better understanding of the mechanisms of myelin repair as well as the identification of potential targets for effective remyelination and neuroprotection for progressive MS.

Age-dependent metabolic effects of second-generation antipsychotics in second-generation antipsychotic-naïve French Canadian patients.

BACKGROUND: Patients receiving second-generation antipsychotics (SGAs) may experience secondary metabolic effects such as weight gain, as well as changes in lipid and glucose metabolism. These effects are well documented in adults; however, fewer studies are available concerning their occurrence and their evolution in children and adolescents. OBJECTIVE: The aim of this study was to determine if there is an age-dependent variation in the metabolic effects of SGAs in a drug-naïve population. METHODS: Charts of 232 French Canadian patients participating in a program monitoring the metabolic effects of SGAs were retrospectively reviewed. A total of 85 SGA-naïve patients were selected, including 58 youths and 27 adults. Changes, relative to baseline, in weight, body mass index, lipid metabolism (total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglyceride), and fasting blood glucose were assessed, with follow-up at 3, 6, 12, and 24 months. RESULTS: With respect to weight gain, in both the youth and adult groups, body mass index significantly increased from baseline at 3 months (10.1% [p < 0.0001] and 12.2% [p < 0.0001], respectively) and 6 months (11.8% [p < 0.0001] and 13.1% [p < 0.0001], respectively). With respect to lipid metabolism, in the youth group, there was no significant change. In the adult group, there was a significant increase at 3 and 6 months in total cholesterol (24.0% [p = 0.004] and 24.1% [p = 0.0006], respectively), low-density lipoprotein (26.8% [p = 0.019] and 30.1% [p = 0.010], respectively), and high-density lipoprotein (10.2% [p = 0.04] and 17.1% [p = 0.005], respectively). There was no significant change in triglyceride and glucose metabolism in both groups. CONCLUSIONS: Our results confirm the age-independent effects of SGA on weight gain. However, more data are needed to explore the age effect on glucose and lipid metabolism.