An indispensable role of macrophages in bone repair has been well recognized. Previous data have demonstrated the copresence of M1 macrophages and mesenchymal stem cells (MSCs) during the proinflammatory stage of bone repair. However, the exact role of M1 macrophages in MSC function and bone repair is unknown. This study aimed to define the role of M1 macrophages at bone injury sites via the function of 1,25-Dihydroxyvitamin D (1,25[OH] ₂ D) in suppressing M1 but promoting M2 differentiation. We showed that 1,25(OH) ₂ D suppressed M1 macrophage–mediated enhancement of MSC migration. Additionally, 1,25(OH) ₂ D inhibited M1 macrophage secretion of osteogenic proteins (i.e., Oncostatin M, TNF-α, and IL-6). Importantly, the 1,25(OH) ₂ D-mediated suppression of osteogenic function in M1 macrophages at the proinflammatory stage was associated with 1,25(OH) ₂ D-mediated reduction of MSC abundance, compromised osteogenic potential of MSCs, and impairment of fracture repair. Furthermore, outside the proinflammatory stage, 1,25(OH) ₂ D treatment did not suppress fracture repair. Accordingly, our data support 2 conclusions: (a) M1 macrophages are important for the recruitment and osteogenic priming of MSCs and, hence, are necessary for fracture repair, and (b) under vitamin D–sufficient conditions, 1,25(OH) ₂ D treatment is unnecessary and can be detrimental if provided during the proinflammatory stage of fracture healing.

A novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is causing the worldwide coronavirus disease 2019 (COVID-19) outbreak with high mortality. A unique finding among COVID-19 patients was a decline of eosinophil levels (eosinopenia). However, results from previous studies on the relationship between eosinopenia and disease severity were inconsistent. The objective of this study is to determine the relationship between eosinopenia and COVID-19 mortality as well as the clinical conditions that could potentially lead to mortality. One hundred ninety patients diagnosed as moderate, severe, or critical COVID-19 at hospital admission were enrolled. Data collected from patients’ medical records on the second day after hospital admission included medical histories, clinical symptoms, chest images of computed tomography (CT), laboratory examinations, and outcomes. Eosinophil levels were significantly lower in patients with critical disease, when compared to those with moderate and severe diseases. After controlled for confounding factors, ie, age, gender, hypertension, coronary heart disease, diabetes, and chronic lung disease, a progressive decline of eosinophil levels was independently associated with mortality. Moreover, eosinophil levels significantly and positively correlated with platelet and D-dimer levels but significantly and inversely correlated with serum levels of urea, creatinine, aspartate aminotransferase, lactate dehydrogenase, and creatine kinase. Eosinopenia, if progressively worsening, indicates that COVID-19 patients may progress to critical disease and have a significantly higher chance of mortality. Additionally, eosinopenia correlates with biomarkers of coagulation disorder and those of tissue damage in kidney, liver, and other tissues.

This study identifies that cyclooxygenase 2 targets CD90 ⁺ skeletal stem cells in fracture sites to accelerate fracture repair.

Current therapies for gut inflammation have not reached the desired specificity and are attended by unintended immune suppression. This study aimed to provide evidence for supporting a hypothesis that direct in vivo augmentation of the induction of gut-homing regulatory T (Treg) cells is a strategy of expected specificity for the treatment of chronic intestinal inflammation (e.g., inflammatory bowel disease). We showed that dendritic cells (DCs), engineered to de novo produce high concentrations of both 1,25-dihydroxyvitamin D, the active vitamin D metabolite, and retinoic acid, an active vitamin A metabolite, augmented the induction of T cells that express both the regulatory molecule Foxp3 and the gut-homing receptor CCR9 in vitro and in vivo. In vivo, the newly generated Ag-specific Foxp3+ T cells homed to intestines. Additionally, transfer of such engineered DCs robustly suppressed ongoing experimental colitis. Moreover, CD4+ T cells from spleens of the mice transferred with the engineered DCs suppressed experimental colitis in syngeneic hosts. The data suggest that the engineered DCs enhance regulatory function in CD4+ T cell population in peripheral lymphoid tissues. Finally, we showed that colitis suppression following in vivo transfer of the engineered DCs was significantly reduced when Foxp3+ Treg cells were depleted. The data indicate that maximal colitis suppression mediated by the engineered DCs requires Treg cells. Collectively, our data support that DCs de novo overproducing both 1,25-dihydroxyvitamin D and retinoic acid are a promising novel therapy for chronic intestinal inflammation.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system and is caused by an aberrant immune response to myelin sheath. Disease-modifying medications, which mainly aim to suppress such aberrant immune response, have significantly improved MS treatment. However, the disease severity continues to worsen. In contrast, progressively more data suggest that 1,25-dihydroxyvitamin D or 1,25(OH)₂D, i.e., the active vitamin D, suppresses the differentiation of potentially pathogenic T cells associated with MS, enhances the differentiation of regulatory T cells that suppress the pathogenic T cells, and promotes remyelination. These novel 1,25(OH)₂D functions have encouraged investigators to develop vitamin D as a potential therapy for MS. However, because of the hypercalcemia that is associated with high 1,25(OH)₂D concentrations, supplementation of native vitamin D has been a major focus in clinical trials for the treatment of MS, but such trials have produced mixed data. In this article, we will review current progress in the supplementation of different vitamin D forms for the treatment of experimental autoimmune encephalomyelitis (i.e., an MS animal model) as well as MS. Furthermore, we will review alternative strategies that our laboratory and others are pursuing in an attempt to circumvent the hurdles that are hampering the effective use of vitamin D as a potential therapy for MS.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Available drugs aim to suppress gut inflammation. These drugs have significantly delayed disease progression and improved patients’ quality of life. However, the disease continues to progress, underscoring the need to develop novel therapies. Aside from chronic gut inflammation, IBD patients also experience a leaky gut problem due to damage to the intestinal epithelial layer. In this regard, epithelial regeneration and repair are mediated by intestinal stem cells. However, no therapies are available to directly enhance the intestinal stem cells’ regenerative and repair function. Recently, it was shown that active vitamin D, i.e., 1,25-dihydroxyvitamin D or 1,25(OH)₂D, was necessary to maintain Lgr5⁺ intestinal stem cells, actively cycling under physiological conditions. In this study, we used two strategies to investigate the role of 1,25(OH)₂D in intestinal stem cells’ regenerative function. First, to avoid the side effects of systemic high 1,25(OH)₂D conditions, we used our recently developed novel strategy to deliver locally high 1,25(OH)₂D concentrations specifically to inflamed intestines. Second, because of the Lgr5⁺ intestinal stem cells’ active cycling status, we used a pulse-and-chase strategy via 5-bromo-2′-deoxyuridine (BrdU) labeling to trace the Lgr5⁺ stem cells through the whole epithelial regeneration process. Our data showed that locally high 1,25(OH)₂D concentrations enhanced intestinal stem cell migration. Additionally, the migrated cells differentiated into mature epithelial cells. Our data, therefore, suggest that local delivery of high 1,25(OH)₂D concentrations is a promising strategy to augment intestinal epithelial repair in IBD patients.