Hypoxia inducible factor 2α promotes tolerogenic macrophage development during cardiac transplantation through transcriptional regulation of colony stimulating factor 1 receptor.

Solid organ transplantation mobilizes myeloid cells, including monocytes and macrophages, which are central protagonists of allograft rejection. However, myeloid cells can also be functionally reprogrammed by perioperative costimulatory blockade to promote a state of transplantation tolerance. Transplantation tolerance holds promise to reduce complications from chronic immunosuppression and promote long-term survival in transplant recipients. We sought to identify different mediators of transplantation tolerance by performing single-cell RNA sequencing of acute rejecting or tolerized cardiac allografts. This led to the unbiased identification of the transcription factor, hypoxia inducible factor (HIF)-2α, in a subset of tolerogenic monocytes. Using flow cytometric analyses and mice with conditional loss or gain of function, we uncovered that myeloid cell expression of HIF-2α was required for costimulatory blockade-induced transplantation tolerance. While HIF-2α was dispensable for mobilization of tolerogenic monocytes, which were sourced in part from the spleen, it promoted the expression of colony stimulating factor 1 receptor (CSF1R). CSF1R mediates monocyte differentiation into tolerogenic macrophages and was found to be a direct transcriptional target of HIF-2α in splenic monocytes. Administration of the HIF stabilizer, roxadustat, within micelles to target myeloid cells, increased HIF-2α in splenic monocytes, which was associated with increased CSF1R expression and enhanced cardiac allograft survival. These data support further exploration of HIF-2α activation in myeloid cells as a therapeutic strategy for transplantation tolerance.

Diagnosis and Management of Cardiovascular Risk in Individuals With Spinal Cord Injury: A Narrative Review.

More than 16 000 Americans experience spinal cord injury (SCI), resulting in chronic disability and other secondary sequelae, each year. Improvements in acute medical management have increased life expectancy. Cardiovascular disease is a leading cause of death in this population, and seems to occur earlier in individuals with SCI compared with the general population. People with SCI experience a high burden of traditional cardiovascular disease risk factors, including dyslipidemia and diabetes, and demonstrate anatomic, metabolic, and physiologic changes alongside stark reductions in physical activity after injury. They also experience multiple, complex barriers to care relating to disability and, in many cases, compounding effects of intersecting racial and socioeconomic health inequities. Given this combination of risk factors, some investigators have proposed that people with SCI are at increased risk for cardiovascular disease, beyond that associated with traditional risk factors, and SCI could be considered a risk-enhancing factor, analogous to other risk-enhancing factors defined by the 2019 American Heart Association/American College of Cardiology Primary Prevention Guidelines. However, more research is needed in this population to clarify the role of traditional risk factors, novel risk factors, health care access, social determinants of health, and intersectionality of disability, race, and socioeconomic status. There is an urgent need for primary care physicians and cardiologists to have awareness of the importance of timely diagnosis and management of cardiac risk factors for people with SCI.

Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance.

Recipient infusion of donor apoptotic cells is an emerging strategy for inducing robust transplantation tolerance. Daily clearance of billions of self-apoptotic cells relies on homeostatic engagement of phagocytic receptors, in particular, receptors of the tyrosine kinase family TAM (Tyro3, Axl, and MerTK), to maintain self-tolerance. However, an outstanding question is if allogeneic apoptotic cells trigger the same receptor system for inducing allogeneic tolerance. Here, we employed allogeneic apoptotic splenocytes and discovered that the efferocytic receptor MerTK on recipient phagocytes is a critical mediator for transplantation tolerance induced by this strategy. Our findings indicate that the tolerogenic properties of allogeneic apoptotic splenocytes require MerTK transmission of intracellular signaling to suppress the production of inflammatory cytokine interferon α (IFN-α). We further demonstrate that MerTK is crucial for subsequent expansion of myeloid-derived suppressor cells and for promoting their immunomodulatory function, including maintaining graft-infiltrating CD4+ CD25+ Foxp3+ regulatory T cells. Consequently, recipient MerTK deficiency resulted in failure of tolerance by donor apoptotic cells, and this failure could be effectively rescued by IFN-α receptor blockade. These findings underscore the importance of the efferocytic receptor MerTK in mediating transplantation tolerance by donor apoptotic cells and implicate MerTK agonism as a promising target for promoting transplantation tolerance.

Disability's absence from admissions nondiscrimination and recruitment initiatives in Top-Tier US allopathic medical schools.

BACKGROUND: Diversity in medical school students is essential to ensure that future physicians can care for a range of patients from different backgrounds. However, disability is often overlooked and there are potential examples of discrimination in US medical schools. OBJECTIVE: To determine if students with disabilities are included in online recruitment, diversity equity and inclusion (DEI), or nondiscrimination materials for US allopathic medical schools. METHODS: In this descriptive study, the authors reviewed publicly available data from websites of the top ranked 51 US allopathic medical schools to assess inclusion of disability in recruitment efforts or antidiscrimination statements. RESULTS: The results showed that just under one third of these schools (31 %) mention disability within their DEI or published recruitment efforts. Most commonly (27.5 %), disability is mentioned in a general diversity statement. CONCLUSIONS: These findings suggest that there is a need for greater inclusion of disability in US medical schools' recruitment efforts. This is essential to ensure that people with disabilities are not discriminated against in medical school applications and is one of many factors that will contribute to future physicians being prepared to care for patients with disabilities.

Document analysis of adaptive sport opportunities at Division-1 universities in the United States.

BACKGROUND: Individuals with disabilities are less likely to participate in physical activity, with the greatest decline in participation during college years. Despite known health benefits, there are significant barriers that limit sport and exercise participation for students with disabilities, including adaptive access. To our knowledge, there has been no comprehensive review conducted to examine the number of adaptive sport offerings on a collegiate level. OBJECTIVE: Assess the availability of adaptive sport opportunities for students at National Collegiate Athletic Association (NCAA) Division-1 Universities to better understand university-affiliated adaptive sport opportunity for students. METHODS: Website document analysis was conducted by systematically querying the general homepage, athletics page, and campus recreation websites of each NCAA Division-1 University in the United States (US). Institutional and sport-related characteristics were recorded. RESULTS: Of the 358 NCAA Division-1 Universities, 20.4 % (73/358) marketed adaptive sport opportunities (recreational, club, and/or intercollegiate), with 3.9 % (11/358) acknowledging intercollegiate adaptive sport programs on their websites. Five percent (6/121) of private institutions, and 28.3 % (67/237) of public institutions reported adaptive sport opportunities. The Northeast region had the fewest number of institutions reporting adaptive sport offerings (4/67, 6.0 %). The most commonly offered sport was adaptive recreation (36/358, 10.2 %), followed by wheelchair basketball (26/358, 7.4 %). CONCLUSION: Over three-quarters of Division-1 Universities in the US lack an online description of adaptive sport opportunity, highlighting the need for expanded resourcing and marketing of adaptive sport at the university level. Future studies are necessary to identify appropriate strategies to effectively promote sport, maximize participation and improve social inclusion.

Immunometabolism at the Heart of Cardiovascular Disease.

Immune cell function among the myocardium, now more than ever, is appreciated to regulate cardiac function and pathophysiology. This is the case for both innate immunity, which includes neutrophils, monocytes, dendritic cells, and macrophages, as well as adaptive immunity, which includes T cells and B cells. This function is fueled by cell-intrinsic shifts in metabolism, such as glycolysis and oxidative phosphorylation, as well as metabolite availability, which originates from the surrounding extracellular milieu and varies during ischemia and metabolic syndrome. Immune cell crosstalk with cardiac parenchymal cells, such as cardiomyocytes and fibroblasts, is also regulated by complex cellular metabolic circuits. Although our understanding of immunometabolism has advanced rapidly over the past decade, in part through valuable insights made in cultured cells, there remains much to learn about contributions of in vivo immunometabolism and directly within the myocardium. Insight into such fundamental cell and molecular mechanisms holds potential to inform interventions that shift the balance of immunometabolism from maladaptive to cardioprotective and potentially even regenerative. Herein, we review our current working understanding of immunometabolism, specifically in the settings of sterile ischemic cardiac injury or cardiometabolic disease, both of which contribute to the onset of heart failure. We also discuss current gaps in knowledge in this context and therapeutic implications.

Student-driven disability advocacy and education within the health professions: pilot survey results from a single-day virtual conference.

BACKGROUND: Health professional programs can promote equitable healthcare delivery but few programs include disability in these efforts. Limited opportunities exist for health professional students to engage with disability education within the classroom or beyond. The Disability Advocacy Coalition in Medicine (DAC Med) is a national interprofessional student-led organization which hosted a virtual conference for health professional students in October 2021. We describe the impact of this single-day virtual conference on learning and the current state of disability education across health professional programs. METHODS: This cross-sectional study utilized a 17-item post-conference survey. A 5-point Likert scale-based survey was distributed to conference registrants. Survey parameters included background in disability advocacy, curricular exposure to disability, and impact of the conference. RESULTS: Twenty-four conference attendees completed the survey. Participants were enrolled in audiology, genetic counseling, medical, medical scientist, nursing, prosthetics and orthotics, public health, and 'other' health programs. Most participants (58.3%) reported not having a strong background in disability advocacy before the conference, with 26.1% indicating they learned about ableism in their program's curriculum. Almost all students (91.6%) attended the conference to learn how to be a better advocate for patients and peers with disabilities, and 95.8% reported that the conference provided this knowledge. Eighty-eight percent of participants agreed that they acquired additional resources to better care for patients with disabilities. CONCLUSIONS: Few health professional students learn about disability in their curriculum. Single-day virtual, interactive conferences are effective in providing advocacy resources and empowering students to employ them.

Alloantigen Infusion Activates the Transcriptome of Type 2 Conventional Dendritic Cells.

Recent studies have revealed novel molecular mechanisms by which innate monocytic cells acutely recognize and respond to alloantigen with significance to allograft rejection and tolerance. What remains unclear is the single-cell heterogeneity of the innate alloresponse, particularly the contribution of dendritic cell (DC) subsets. To investigate the response of these cells to exposure of alloantigen, C57BL/6J mice were administered live allogenic BALB/cJ splenic murine cells versus isogenic cells. In parallel, we infused apoptotic allogenic and isogenic cells, which have been reported to modulate immunity. Forty-eight hours after injection, recipient spleens were harvested, enriched for DCs, and subjected to single-cell mRNA sequencing. Injection of live cells induced a greater transcriptional change across DC subsets compared with apoptotic cells. In the setting of live cell infusion, type 2 conventional DCs (cDC2s) were most transcriptionally responsive with a Ccr2+ cDC2 subcluster uniquely responding to the presence of alloantigen compared with the isogenic control. In vitro experimentation confirmed unique activation of CCR2+ cDC2s following alloantigen exposure. Candidate receptors of allorecognition in other innate populations were interrogated and A type paired Ig-like receptors were found to be increased in the cDC2 population following alloexposure. These results illuminate previously unclear distinctions between therapeutic infusions of live versus apoptotic allogenic cells and suggest a role for cDC2s in innate allorecognition. More critically, these studies allow for future interrogation of the transcriptional response of immune cells in the setting of alloantigen exposure in vivo, encouraging assessment of novel pathways and previously unexamined receptors in this setting.

Emerging Roles for Dendritic Cells in Heart Failure.

The field of cardio-immunology has emerged from discoveries that define roles for innate and adaptive immune responses associated with myocardial inflammation and heart failure. Dendritic cells (DCs) comprise an important cellular compartment that contributes to systemic immune surveillance at the junction of innate and adaptive immunity. Once described as a singular immune subset, we now appreciate that DCs consist of a heterogeneous pool of subpopulations, each with distinct effector functions that can uniquely regulate the acute and chronic inflammatory response. Nevertheless, the cardiovascular-specific context involving DCs in negotiating the biological response to myocardial injury is not well understood. Herein, we review our current understanding of the role of DCs in cardiac inflammation and heart failure, including gaps in knowledge and clinical relevance.

Dismantle Ableism, Accept Disability: Making the Case for Anti-Ableism in Medical Education.

There currently exists an exciting impetus for increased diversity among medical trainees and improved equity in medical care received by patients. Yet, inclusion of disability within these efforts is often forgotten, allowing the current cultural narrative of ableism to shape medical training. National structural challenges as early as medical school admissions and ableist barriers throughout the educational pipeline have yielded 1) a concerningly low prevalence of medical students and physicians in the US who identify as disabled and 2) propagation of systemic misunderstandings on disability in our healthcare system. This perspective addresses the need for a re-evaluation of diversity in medicine which includes ability status and a commitment to anti-ableism as a critical part of the conversation. We propose reforms and important considerations that could have meaningful implications necessary for improving the culture of disability inclusion in medical education.

Bone marrow-derived AXL tyrosine kinase promotes mitogenic crosstalk and cardiac allograft vasculopathy.

Cardiac Allograft Vasculopathy (CAV) is a leading contributor to late transplant rejection. Although implicated, the mechanisms by which bone marrow-derived cells promote CAV remain unclear. Emerging evidence implicates the cell surface receptor tyrosine kinase AXL to be elevated in rejecting human allografts. AXL protein is found on multiple cell types, including bone marrow-derived myeloid cells. The causal role of AXL from this compartment and during transplant is largely unknown. This is important because AXL is a key regulator of myeloid inflammation. Utilizing experimental chimeras deficient in the bone marrow-derived Axl gene, we report that Axl antagonizes cardiac allograft survival and promotes CAV. Flow cytometric and histologic analyses of Axl-deficient transplant recipients revealed reductions in both allograft immune cell accumulation and vascular intimal thickness. Co-culture experiments designed to identify cell-intrinsic functions of Axl uncovered complementary cell-proliferative pathways by which Axl promotes CAV-associated inflammation. Specifically, Axl-deficient myeloid cells were less efficient at increasing the replication of both antigen-specific T cells and vascular smooth muscle cells (VSMCs), the latter a key hallmark of CAV. For the latter, we discovered that Axl-was required to amass the VSMC mitogen Platelet-Derived Growth Factor. Taken together, our studies reveal a new role for myeloid Axl in the progression of CAV and mitogenic crosstalk. Inhibition of AXL-protein, in combination with current standards of care, is a candidate strategy to prolong cardiac allograft survival.

Innate Functions of Dendritic Cell Subsets in Cardiac Allograft Tolerance.

Survival rates after heart transplant have significantly improved over the last decade. Nevertheless, long-term allograft viability after 10 years remains poor and the sequelae of transplant-associated immunosuppression increases morbidity. Although several studies have implicated roles for lymphocyte-mediated rejection, less is understood with respect to non-major histocompatibility, and innate immune reactivity, which influence graft viability. As immature and mature dendritic cells (DCs) engage in both Major Histocompatibility Complex (MHC)-dependent and MHC-independent immune responses, these cells are at the crossroads of therapeutic strategies that seek to achieve both allograft tolerance and suppression of innate immunity to the allograft. Here we review emerging roles of DC subsets and their molecular protagonists during allograft tolerance and allograft rejection, with a focus on cardiac transplant. New insight into emerging DC subsets in transplant will inform novel strategies for operational tolerance and amelioration of cardiac vasculopathy.

Stress-related memories disrupt sociability and associated patterning of hippocampal activity: a role of hilar oxytocin receptor-positive interneurons.

In susceptible individuals, memories of stressful experiences can give rise to debilitating socio-affective symptoms. This occurs even when the ability to retrieve such memories is limited, as seen in patients suffering from traumatic amnesia. We therefore hypothesized that the encoding, rather than retrieval, mechanisms of stress-related memories underlie their impact on social and emotional behavior. To test this hypothesis, we used combinations of stress-enhanced and state-dependent fear conditioning, which engage different encoding mechanisms for the formation of stress-related memories. We found that the encoding of stress-enhanced state-dependent memories robustly and sex specifically impairs sociability in male mice and disrupts the asymmetry of dentate gyrus (DG)/CA3 activity accompanying social interactions. These deficits were restored by chemogenetic inactivation of oxytocin receptor-positive interneurons localized in the hilus (Oxtr-HI), and by inactivation of dorsohippocampal efferents to the caudal lateral septum. Together, our data suggest that disrupted patterning of dorsohippocampal DG/CA3 activity underlies stress-induced sociability deficits, and that Oxtr-HI can be a cellular target for improving these deficits.