Elevated Galectin-3 Is Associated with Aging, Multiple Sclerosis, and Oxidized Phosphatidylcholine-Induced Neurodegeneration.

Aging is a significant risk factor associated with the progression of CNS neurodegenerative diseases including multiple sclerosis (MS). Microglia, the resident macrophages of the CNS parenchyma, are a major population of immune cells that accumulate in MS lesions. While they normally regulate tissue homeostasis and facilitate the clearance of neurotoxic molecules including oxidized phosphatidylcholines (OxPCs), their transcriptome and neuroprotective functions are reprogrammed by aging. Thus, determining the factors that instigate aging associated microglia dysfunction can lead to new insights for promoting CNS repair and for halting MS disease progression. Through single-cell RNA sequencing (scRNAseq), we identified Lgals3, which encodes for galectin-3 (Gal3), as an age upregulated gene by microglia responding to OxPC. Consistently, excess Gal3 accumulated in OxPC and lysolecithin-induced focal spinal cord white matter (SCWM) lesions of middle-aged mice compared with young mice. Gal3 was also elevated in mouse experimental autoimmune encephalomyelitis (EAE) lesions and more importantly in MS brain lesions from two male and one female individuals. While Gal3 delivery alone into the mouse spinal cord did not induce damage, its co-delivery with OxPC increased cleaved caspase 3 and IL-1ß within white matter lesions and exacerbated OxPC-induced injury. Conversely, OxPC-mediated neurodegeneration was reduced in Gal3-/- mice compared with Gal3+/+ mice. Thus, Gal3 is associated with increased neuroinflammation and neurodegeneration and its overexpression by microglia/macrophages may be detrimental for lesions within the aging CNS.SIGNIFICANCE STATEMENT Aging accelerates the progression of neurodegenerative diseases such as multiple sclerosis (MS). Understanding the molecular mechanisms of aging that increases the susceptibility of the CNS to damage could lead to new strategies to manage MS progression. Here, we highlight that microglia/macrophage-associated galectin-3 (Gal3) was upregulated with age exacerbated neurodegeneration in the mouse spinal cord white matter (SCWM) and in MS lesions. More importantly, co-injection of Gal3 with oxidized phosphatidylcholines (OxPCs), which are neurotoxic lipids found in MS lesions, caused greater neurodegeneration compared with injection of OxPC alone, whereas genetic loss of Gal3 reduced OxPC damage. These results demonstrate that Gal3 overexpression is detrimental to CNS lesions and suggest its deposition in MS lesions may contribute to neurodegeneration.

Emerging role of galectin 3 in neuroinflammation and neurodegeneration.

Neuroinflammation and neurodegeneration are key processes that mediate the development and progression of neurological diseases. However, the mechanisms modulating these processes in different diseases remain incompletely understood. Advances in single cell based multi-omic analyses have helped to identify distinct molecular signatures such as Lgals3 that is associated with neuroinflammation and neurodegeneration in the central nervous system (CNS). Lgals3 encodes galectin-3 (Gal3), a ß-galactoside and glycan binding glycoprotein that is frequently upregulated by reactive microglia/macrophages in the CNS during various neurological diseases. While Gal3 has previously been associated with non-CNS inflammatory and fibrotic diseases, recent studies highlight Gal3 as a prominent regulator of inflammation and neuroaxonal damage in the CNS during diseases such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease. In this review, we summarize the pleiotropic functions of Gal3 and discuss evidence that demonstrates its detrimental role in neuroinflammation and neurodegeneration during different neurological diseases. We also consider the challenges of translating preclinical observations into targeting Gal3 in the human CNS.

Osteopathic manipulative treatment of patients with chronic low back pain in the United States: a retrospective cohort study.

CONTEXT: The practice of osteopathic manipulative treatment (OMT) varies substantially across nations. Much of this variability may be attributed to disparate international educational, licensing, and regulatory environments that govern the practice of osteopathy by nonphysicians. This is in contrast with the United States, where osteopathic physicians are trained to integrate OMT as part of comprehensive patient management. OBJECTIVES: This study will analyze the factors associated with OMT use and its outcomes when integrated within the overall medical care for chronic low back pain (CLBP) provided by osteopathic physicians in the United States. METHODS: A retrospective cohort study was conducted within the Pain Registry for Epidemiological, Clinical, and Interventional Studies and Innovation (PRECISION) from April 2016 through April 2022 to study the effectiveness of OMT integrated within medical care provided by osteopathic physicians. The outcome measures, which included pain intensity, pain impact, physical function, and health-related quality of life, were assessed with the National Institutes of Health Minimum Dataset, Patient-Reported Outcomes Measurement Information System, and Roland-Morris Disability Questionnaire. RESULTS: A total of 1,358 adults with CLBP entered the cohort (mean age, 53.2 years; 74.4% female), 913 completed the final quarterly encounter, 348 were in various stages of follow-up, and 97 had withdrawn. Blacks (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.21-0.63; p<0.001), cigarette smokers (OR, 0.56; 95% CI, 0.33-0.93; p=0.02), and nonsteroidal anti-inflammatory drug users (OR, 0.59; 95% CI, 0.43-0.81; p=0.001) were less likely to have utilized OMT in the multivariable analysis. Mean between-group differences among 753 participants with no OMT crossover and complete follow-up favored OMT: 1.02 (95% CI, 0.63-1.42; p<0.001) for pain intensity; 5.12 (95% CI, 3.09-7.16; p<0.001) for pain impact; 3.59 (95% CI, 2.23-4.95; p<0.001) for physical function, and 2.73 (95% CI, 1.19-4.27; p<0.001) for health-related quality of life. Analyses involving propensity-score adjustment and inclusion of participants with missing data yielded similar conclusions. None of 12 prespecified participant characteristics demonstrated an OMT interaction effect. CONCLUSIONS: OMT integrated within medical care provided by osteopathic physicians for CLBP was associated with improved pain and related outcomes. Its use may be facilitated by the growing osteopathic physician workforce in the United States and adherence to relevant clinical practice guidelines.