Impact of Federal, State, and Local Housing Policies on Disparities in Cardiovascular Disease in Black/African American Men and Women: From Policy to Pathways to Biology.

Racist and discriminatory federal, state, and local housing policies significantly contribute to disparities in cardiovascular disease incidence and mortality for individuals that self-identify as Black or African American. Here we highlight three key housing policies - "redlining," zoning, and the construction of highways - which have wrought a powerful, sustained, and destructive impact on cardiovascular health in Black/African American communities. Redlining and highway construction policies have restricted access to quality health care, increased exposure to carcinogens such as PM2.5, and increased exposure to extreme heat. At the root of these policy decisions are longstanding, toxic societal factors including racism, segregation, and discrimination, which also serve to perpetuate racial inequities in cardiovascular health. Here, we review these societal and structural factors and then link them with biological processes such as telomere shortening, allostatic load, oxidative stress, and tissue inflammation. Lastly, we focus on the impact of inflammation on the immune system and the molecular mechanisms by which the inflamed immune microenvironment promotes the formation of atherosclerotic plaques. We propose that racial residential segregation and discrimination increases tissue inflammation and cytokine production, resulting in dysregulated immune signaling, which promotes plaque formation and cardiovascular disease. This framework has the power to link structural racism not only to cardiovascular disease, but also to cancer.

Increased inflammatory low-density neutrophils in severe obesity and effect of bariatric surgery: Results from case-control and prospective cohort studies.

BACKGROUND: Low-density neutrophils (LDN) are increased in several inflammatory diseases and may also play a role in the low-grade chronic inflammation associated with obesity. Here we explored their role in obesity, determined their gene signatures, and assessed the effect of bariatric surgery. METHODS: We compared the number, function, and gene expression profiles of circulating LDN in morbidly obese patients (MOP, n=27; body mass index (BMI) > 40 Kg/m2) and normal-weight controls (NWC, n=20; BMI < 25 Kg/m2) in a case-control study. Additionally, in a prospective longitudinal study, we measured changes in the frequency of LDN after bariatric surgery (n=36) and tested for associations with metabolic and inflammatory parameters. FINDINGS: LDN and inflammatory markers were significantly increased in MOP compared to NWC. Transcriptome analysis showed increased neutrophil-related gene expression signatures associated with inflammation, neutrophil activation, and immunosuppressive function. However, LDN did not suppress T cells proliferation and produced low levels of reactive oxygen species (ROS). Circulating LDN in MOP significantly decreased after bariatric surgery in parallel with BMI, metabolic syndrome, and inflammatory markers. INTERPRETATION: Obesity increases LDN displaying an inflammatory gene signature. Our results suggest that LDN may represent a neutrophil subset associated with chronic inflammation, a feature of obesity that has been previously associated with the appearance and progression of co-morbidities. Furthermore, bariatric surgery, as an efficient therapy for severe obesity, reduces LDN in circulation and improves several components of the metabolic syndrome supporting its recognized anti-inflammatory and beneficial metabolic effects. FUNDING: This work was supported in part by grants from the National Institutes of Health (NIH; 5P30GM114732-02, P20CA233374 - A. Ochoa and L. Miele), Pennington Biomedical NORC (P30DK072476 - E. Ravussin & LSU-NO Stanley S. Scott Cancer Center and Louisiana Clinical and Translational Science Center (LACaTS; U54-GM104940 - J. Kirwan).

Detection of Circulating and Tissue Myeloid-Derived Suppressor Cells (MDSC) by Flow Cytometry.

Flow cytometry allows the multiparameter analysis of heterogeneous cell populations and is an essential tool for detecting and characterizing different cell populations from peripheral blood and dissociated tissues. Myeloid-derived suppressor cells (MDSC) are a heterogeneous and plastic group of myeloid precursors with immune-suppressive capacity, which are a characteristic feature of chronic inflammation, such as cancer. The optimal measurement of MDSC levels could be used as a biomarker for clinicians for prognosis and/or management and for researchers to track and understand the role of MDSC in different pathological diseases.The criteria for defining MDSC include phenotypic surface markers, but ideally should also include the functional immunosuppressive effect on T cells, and, if possible, assessing the main biochemical and molecular features. Two major functional mechanisms to suppress T cell responses are the production of arginase-1 and reactive oxygen species (ROS) molecules. Here is presented a nine-parameter seven-color flow cytometric assay to identify and quantify MDSC from both peripheral blood mononuclear cells (PBMC) and dissociated tissue (e.g., tumor) by using fluorescence-tagged antibodies against surface markers. Also, the intracellular levels of arginase-1 and superoxide (O2-) content were performed to potentially distinguish their functional status.

Myeloid-derived suppressor cells (MDSC): When good intentions go awry.

MDSC are a heterogeneous population of immature myeloid cells that are released by biological stress such as tissue damage and inflammation. Conventionally, MDSC are known for their detrimental role in chronic inflammation and neoplastic conditions. However, their intrinsic functions in immunoregulation, wound healing, and angiogenesis are intended to protect from over-reactive immune responses, maintenance of immunotolerance, tissue repair, and homeostasis. Paradoxically, under certain conditions, MDSC can impair protective immune responses and exacerbate the disease. The transition from protective to harmful MDSC is most likely driven by environmental and epigenetic mechanisms induced by prolonged exposure to unresolved inflammatory triggers. Here, we review several examples of the dual impact of MDSC in conditions such as maternal-fetal tolerance, self-antigens immunotolerance, obesity-associated cancer, sepsis and trauma. Moreover, we also highlighted the evidence indicating that MDSC have a role in COVID-19 pathophysiology. Finally, we have summarized the evidence indicating epigenetic mechanisms associated with MDSC function.

Obesity-Associated Myeloid Immunosuppressive Cells, Key Players in Cancer Risk and Response to Immunotherapy.

Obesity is a risk factor for developing several cancers. The dysfunctional metabolism and chronic activation of inflammatory pathways in obesity create a milieu that supports tumor initiation, progression, and metastasis. Obesity-associated metabolic, endocrine, and inflammatory mediators, besides interacting with cells leading to a malignant transformation, also modify the intrinsic metabolic and functional characteristics of immune myeloid cells. Here, the evidence supporting the hypothesis that obesity metabolically primes and promotes the expansion of myeloid cells with immunosuppressive and pro-oncogenic properties is discussed. In consequence, the accumulation of these cells, such as myeloid-derived suppressor cells and some subtypes of adipose-tissue macrophages, creates a microenvironment conducive to tumor development. In this review, the role of lipids, insulin, and leptin, which are dysregulated in obesity, is emphasized, as well as dietary nutrients in metabolic reprogramming of these myeloid cells. Moreover, emerging evidence indicating that obesity enhances immunotherapy response and hypothesized mechanisms are summarized. Priorities in deeper exploration involving the mechanisms of cross talk between metabolic disorders and myeloid cells related to cancer risk in patients with obesity are highlighted.