Obesity dysregulates B cell populations, which contributes toward poor immunological outcomes. We previously reported that differing B cell subsets are lowered in the bone marrow of obese male mice. ...Here, we focused on how lipid metabolites synthesized from docosahexaenoic acid (DHA) known as specialized pro‐resolving lipid mediators (SPMs) influence specific B cell populations in obese male mice. Metabololipidomics revealed that splenic SPM precursors 14‐hydroxydocosahexaenoic acid (14‐HDHA), 17‐hydroxydocosahexaenoic acid (17‐HDHA), and downstream protectin DX (PDX) were decreased in obese male C57BL/6J mice. Simultaneous administration of these mediators to obese mice rescued major decrements in bone marrow B cells, modest impairments in the spleen, and circulating IgG2c, which is pro‐inflammatory in obesity. In vitro studies with B cells, flow cytometry experiments with ALOX5−/− mice, and lipidomic analyses revealed the lowering of 14‐HDHA/17‐HDHA/PDX and dysregulation of B cell populations in obesity was driven indirectly via B cell extrinsic mechanisms. Notably, the lowering of lipid mediators was associated with an increase in the abundance of n‐6 polyunsaturated fatty acids, which have a high affinity for SPM‐generating enzymes. Subsequent experiments revealed female obese mice generally maintained the levels of SPM precursors, B cell subsets, and antibody levels. Finally, obese human females had increased circulating plasma cells accompanied by ex vivo B cell TNFα and IL‐10 secretion. Collectively, the data demonstrate that DHA‐derived mediators of the SPM pathway control the number of B cell subsets and pro‐inflammatory antibody levels in obese male but not female mice through a defect that is extrinsic to B cells.
DHA‐derived mediators increase select B cell subset numbers and lower circulating pathogenic IgG2c in obese male mice.
Obesity is associated with increased risk for infections and poor responses to vaccinations, which may be due to compromised B cell function. However, there is limited information about the influence ...of obesity on B cell function and underlying factors that modulate B cell responses. Therefore, we studied B cell cytokine secretion and/or Ab production across obesity models. In obese humans, B cell IL-6 secretion was lowered and IgM levels were elevated upon ex vivo anti-BCR/TLR9 stimulation. In murine obesity induced by a high fat diet, ex vivo IgM and IgG were elevated with unstimulated B cells. Furthermore, the high fat diet lowered bone marrow B cell frequency accompanied by diminished transcripts of early lymphoid commitment markers. Murine B cell responses were subsequently investigated upon influenza A/Puerto Rico/8/34 infection using a Western diet model in the absence or presence of docosahexaenoic acid (DHA). DHA, an essential fatty acid with immunomodulatory properties, was tested because its plasma levels are lowered in obesity. Relative to controls, mice consuming the Western diet had diminished Ab titers whereas the Western diet plus DHA improved titers. Mechanistically, DHA did not directly target B cells to elevate Ab levels. Instead, DHA increased the concentration of the downstream specialized proresolving lipid mediators (SPMs) 14-hydroxydocosahexaenoic acid, 17-hydroxydocosahexaenoic acid, and protectin DX. All three SPMs were found to be effective in elevating murine Ab levels upon influenza infection. Collectively, the results demonstrate that B cell responses are impaired across human and mouse obesity models and show that essential fatty acid status is a factor influencing humoral immunity, potentially through an SPM-mediated mechanism.
We report two cases of endovascular intervention for management of cerebral venous sinus thrombosis complicated by an acute intracranial hemorrhage during treatment with therapeutic anticoagulation. ...The first patient developed an acute subdural hematoma with progressive enlargement and was subsequently managed with venous sinus thrombectomy. The second patient developed an intraparenchymal and subdural hematoma and was treated with middle meningeal embolization. Anticoagulation is the primary treatment for cerebral venous sinus thrombosis but also contraindicated in an acute intracranial hemorrhage. In these cases, after endovascular intervention both patients resumed therapeutic anticoagulation without further hematoma expansion or additional invasive interventions. Both patients made an excellent neurological recovery and returned to their baseline functional independent status. Given the need for anticoagulation, endovascular intervention in the form of thrombectomy or middle meningeal artery embolization may be a viable adjuvant to anticoagulation in select patients.
Abstract
Exposure to ozone (O3) induces lung injury, pulmonary inflammation, and alters lipid metabolism. During tissue inflammation, specialized pro-resolving lipid mediators (SPMs) facilitate the ...resolution of inflammation. SPMs regulate the pulmonary immune response during infection and allergic asthma; however, the role of SPMs in O3-induced pulmonary injury and inflammation is unknown. We hypothesize that O3 exposure induces pulmonary inflammation by reducing SPMs. To evaluate this, male C57Bl/6J mice were exposed to filtered air (FA) or 1 ppm O3 for 3 h and necropsied 24 h after exposure. Pulmonary injury/inflammation was determined by bronchoalveolar lavage (BAL) differentials, protein, and lung tissue cytokine expression. SPMs were quantified by liquid chromatography tandem mass spectrometry and SPM receptors leukotriene B4 receptor 1 (BLT-1), formyl peptide receptor 2 (ALX/FPR2), chemokine-like receptor 1 (ChemR23), and SPM-generating enzyme (5-LOX and 12/15-LOX) expression were measured by real time PCR. 24 h post-O3 exposure, BAL PMNs and protein content were significantly increased compared to FA controls. O3-induced lung inflammation was associated with significant decreases in pulmonary SPM precursors (14-HDHA, 17-HDHA), the SPM PDX, and in pulmonary ALX/FPR2, ChemR23, and 12/15-LOX expression. Exogenous administration of 14-HDHA, 17-HDHA, and PDX 1 h prior to O3 exposure rescued pulmonary SPM precursors/SPMs, decreased proinflammatory cytokine and chemokine expression, and decreased BAL macrophages and PMNs. Taken together, these data indicate that O3-mediated SPM reductions may drive O3-induced pulmonary inflammation.
Cardiac phospholipids, notably cardiolipin, undergo acyl chain remodeling and/or loss of content in aging and cardiovascular diseases, which is postulated to mechanistically impair mitochondrial ...function. Less is known about how diet-induced obesity influences cardiac phospholipid acyl chain composition and thus mitochondrial responses. Here we first tested if a high fat diet remodeled murine cardiac mitochondrial phospholipid acyl chain composition and consequently disrupted membrane packing, supercomplex formation and respiratory enzyme activity. Mass spectrometry analyses revealed that mice consuming a high fat diet displayed 0.8–3.3 fold changes in cardiac acyl chain remodeling of cardiolipin, phosphatidylcholine, and phosphatidylethanolamine. Biophysical analysis of monolayers constructed from mitochondrial phospholipids of obese mice showed impairment in the packing properties of the membrane compared to lean mice. However, the high fat diet, relative to the lean controls, had no influence on cardiac mitochondrial supercomplex formation, respiratory enzyme activity, and even respiration. To determine if the effects were tissue specific, we subsequently conducted select studies with liver tissue. Compared to the control diet, the high fat diet remodeled liver mitochondrial phospholipid acyl chain composition by 0.6–5.3-fold with notable increases in n-6 and n-3 polyunsaturation. The remodeling in the liver was accompanied by diminished complex I to III respiratory enzyme activity by 3.5-fold. Finally, qRT-PCR analyses demonstrated an upregulation of liver mRNA levels of tafazzin, which contributes to cardiolipin remodeling. Altogether, these results demonstrate that diet-induced obesity remodels acyl chains in the mitochondrial phospholipidome and exerts tissue specific impairments of respiratory enzyme activity.
Despite the importance of diet in the prevention and management of many common chronic diseases, nutrition training in medicine is largely inadequate in medical school and residency. The emerging ...field of culinary medicine offers an experiential nutrition learning approach with the potential to address the need for improved nutrition training of physicians. Exploring this innovative nutrition training strategy, this scoping review describes the nature of culinary medicine experiences for medical students and resident physicians, their impact on the medical trainees, and barriers and facilitators to their implementation.
This scoping review used the Joanna Briggs Institute methodology for scoping reviews and the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews (PRISMA-ScR) checklist as guides. Eligible publications described the nature, impact, facilitators, and/or barriers of nutrition and food preparation learning experiences for medical students and/or residents. Additional inclusion criteria were location (U.S. or Canada), allopathic or osteopathic, English, human subjects, and publication year (2002 or later). The search strategy included 4 electronic databases. Two reviewers independently screened titles/abstracts and a third reviewer resolved discrepancies. The full-text review consisted of 2 independent reviews with discrepancies resolved by a third reviewer or by consensus if needed, and the research team extracted data from the included articles based on the nature, impact, barriers, and facilitators of culinary medicine experiences for medical trainees.
The publication search resulted in 100 publications describing 116 experiences from 70 institutions. Thirty-seven publications described pilot experiences. Elective/extracurricular and medical student experiences were more common than required and resident experiences, respectively. Experiences varied in logistics, instruction, and curricula. Common themes of tailored culinary medicine experiences included community engagement/service-based learning, interprofessional education, attention to social determinants of health, trainee well-being, and cultural considerations. Program evaluations commonly reported the outcome of experiences on participant attitudes, knowledge, skills, confidence, and behaviors. Frequent barriers to implementation included time, faculty, cost/funding, kitchen space, and institutional support while common facilitators of experiences included funding/donations, collaboratives and partnerships, teaching kitchen access, faculty and institutional support, and trainee advocacy.
Culinary medicine is an innovative approach to address the need and increased demand for improved nutrition training in medicine. The findings from this review can guide medical education stakeholders interested in developing or modifying culinary medicine experiences. Despite barriers to implementation, culinary medicine experiences can be offered in a variety of ways during undergraduate and graduate medical education and can be creatively designed to fulfill some accreditation standards.
Retinoids, natural and synthetic derivatives of vitamin A, induce cellular changes by activating nuclear retinoic acid receptors (RAR) and retinoid X receptors (RXR). Although the ability of ...retinoids to govern gene expression is exploited clinically for cancer therapeutics, the full benefit of retinoid‐based strategies is unrealized due to detrimental side effects. Delineating the receptors that prompt cellular outcomes is critical to advancing retinoid‐based approaches. Here, we identify the receptors that evoke multiple responses in cutaneous T‐cell lymphoma (CTCL). The data demonstrate that RARα drives integrin β7‐dependent adhesion and CCR9‐mediated chemotaxis in CTCL cells. Of note, concomitant activation of RARα and RXR nuclear receptors yielded synergistic increases in adhesion and migration at concentrations where single agents were ineffective. As the established paradigm of retinoid action in CTCL is apoptosis and growth arrest, the role of RARα/RXR in these events was studied. As with adhesion and migration, RARα/RXR synergism prompted apoptosis and dampened CTCL cell proliferation. Strikingly, RARα/RXR synergism induced responses from CTCL cell lines previously reported to be unresponsive to retinoids. These data provide a novel framework that may further refine a proven CTCL therapy.
Abstract only
Obesity promotes a diminished response to vaccinations and infections. Therefore, understanding how obesity targets B cell‐driven humoral immunity, particularly at a mechanistic level, ...is essential to elucidate. Using a murine model, we report that diet‐induced obesity impairs early B cell development and induces a dysfunctional immune response. B cells from obese mice displayed a two‐fold reduction in the number of CD19
+
cells, resulting in decreased frequencies of various B cell subsets in the bone marrow. Early lymphoid commitment markers such as IL7Rα, IL7R, and STAT5 showed significantly decreased expression at the transcript level. In addition, obese mice had reduced mRNA expression of the B cell lymphopoiesis markers, PAX5 and Oct2, compared to controls. Functionally, B cells from obese mice had elevated IgM and IgG levels in the absence of stimulation. When B cells from the obese mice were challenged with anti‐TLR4 or anti‐BCR/TLR9 in vitro, the ability to produce IgM and IgG was diminished. Overall, these findings demonstrate that obesity hinders B cell development and drives a dysregulated immune response, which could contribute to impaired responses to infections and vaccinations.
Support or Funding Information
Supported by NIH R01AT008375 (SRS)
Obesity impairs humoral immunity, which is hypothesized to contribute toward chronic inflammation, poor responses to vaccination, and increased susceptibility to infections. Our research program is ...focused on understanding the mechanisms by which lipid metabolites synthesized from polyunsaturated fatty acids regulate humoral immunity in diet-induced obesity.
Here we used a combination of metabololipidomics and immunological assays to understand how obesity impairs production of key metabolites in the context of inflammation and infection.
Targeted metabololipidomic analyses across tissues revealed a reduction in the production of lipid metabolites known as specialized pro-resolving lipid mediators (SPMs) synthesized from docosahexaenoic acid. Notably, the SPM precursors 14-hydroxydoco-sahexaenoic acid (14-HDHA), 17-hydroxydocosahexaenoic acid (17-HDHA), and downstream protectin DX (PDX) were decreased in the spleens of obese male C57BL/6 J mice. Simultaneous administration of these mediators to obese male mice rescued obesity-driven decrements in the production of B cell subsets accompanied by improvements in the levels of pro-inflammatory antibodies in circulation and in adipose tissue. Administration of 14-HDHA, in particular, also improved antibody levels and the production of antibody secreting cells upon influenza A/Puerto Rico/8/34 infection. A combination of in vitro studies and experiments with 5-lipoxygenase knockouts revealed the lowering of 14-HDHA/17-HDHA/PDX was driven indirectly via B cell extrinsic mechanisms. Finally, comparative studies with female obese mice and humans revealed no impairments in the production of B cell subsets, SPMs, and pro-inflammatory antibodies.
Collectively, the data suggest that metabolites of the SPM family, which are lowered in obesity in a sex-specific manner, are key regulators of humoral immunity. Therefore, targeting the abundance of these metabolites may have therapeutic value for improving inflammatory and infectious outcomes for the obese.
NIH R01AT008375.
Diet‐induced obesity is associated with impaired B‐cell‐driven humoral immunity, which coincides with chronic inflammation and has consequences for responses to infections and vaccinations. Key ...nutritional, cellular, and molecular mechanisms by which obesity may impair aspects of humoral immunity such as B cell development, class switch recombination, and formation of long‐lived antibody secreting cells are reviewed. A key theme to emerge is the central role of white adipose tissue on the formation and function of pro‐inflammatory B cell subsets that exacerbate insulin resistance. The underlying role of select hormones such as leptin is highlighted, which may be driving the formation of pro‐inflammatory B cells in the absence of antigen stimulation. This review also extensively covers the regulatory role of lipid metabolites such as prostaglandins and specialized pro‐resolving mediators (SPMs) that are synthesized from polyunsaturated fatty acids. Notably, SPM biosynthesis is impaired in obesity and contributes toward impaired antibody production. Future directions for research, including avenues for therapeutic intervention, are included.
This review covers experimental data on how obesity impairs key aspects of humoral immunity. Notably, results from human and rodent studies suggest that leptin may be driving B lymphocytes to become pro‐inflammatory and secrete auto‐antibodies. The review also discusses how metabolites derived from polyunsaturated fatty acids regulate antigen‐specific antibody levels.
PDF
