bims-traimu 2023-03-26 papers

Issue of 2023–03–26
three papers selected by
Yantong Wan, Southern Medical University

Blood. 2023 Mar 23. pii: blood.2022018026. [Epub ahead of print]

Macrophage metabolic rewiring improves heme-suppressed efferocytosis and tissue damage in sickle cell disease.

Richa Sharma, Ada Antypiuk, S Zebulon Vance, Deepa Manwani, Quentinn Pearce, James Eric Cox, Xiuli An, Karina Yazdanbakhsh, Francesca Vinchi.

Sickle cell disease (SCD) is hallmarked by an underlying chronic inflammatory condition, which is contributed by heme-activated pro-inflammatory macrophages. While previous studies addressed heme ability to stimulate macrophage inflammatory skewing through TLR4/ROS signaling, how heme alters cell functional properties remains unexplored. Macrophage-mediated immune cell recruitment and apoptotic cell (AC) clearance are relevant in the context of SCD, where tissue damage, cell apoptosis and inflammation occur due to vasoocclusive episodes, hypoxia and ischemic injury. Here we show that heme strongly alters macrophage functional response to AC damage by exacerbating immune cell recruitment and impairing cell efferocytic capacity. In SCD, heme-driven excessive leukocyte influx and defective efferocytosis contribute to exacerbated tissue damage and sustained inflammation. Mechanistically, these events depend on heme-mediated activation of TLR4 signaling and suppression of the transcription factor PPARg and its coactivator PGC1a. These changes reduce efferocytic receptor expression and promote mitochondrial remodeling, resulting in a coordinated functional and metabolic reprogramming of macrophages. Overall, this results in limited AC engulfment, impaired metabolic shift to mitochondrial fatty acid b-oxidation and ultimately reduced secretion of the anti-inflammatory cytokines IL-4 and IL-10, with consequent inhibition of continual efferocytosis, resolution of inflammation and tissue repair. We further demonstrate that impaired phagocytic capacity is recapitulated by macrophage exposure to sickle patients'plasma and improved by hemopexin-mediated heme scavenging, PPARg agonists or IL-4 exposure through functional and metabolic macrophage rewiring. Our data indicate that therapeutic improvement of heme-altered macrophage functional properties via heme scavenging or PGC1a/PPARg modulation significantly ameliorate tissue damage associated with SCD pathophysiology.

DOI: https://doi.org/10.1182/blood.2022018026

Vet Immunol Immunopathol. 2023 Mar 16. pii: S0165-2427(23)00033-8. [Epub ahead of print]259 110579

Immunotolerance of dairy heifers in response to repeated exposure to bacterial lipopolysaccharide endotoxin.

T Sullivan, A Sharma, K Lamers, B A Mallard, A Cánovas, N A Karrow.

Dairy cattle face a variety of stressful events on a daily basis. More specifically, climate change has resulted in more frequent heat stress events that increase the incidence of chronic bacterial infections by inducing conditions like leaky gut syndrome, whereby the integrity of the intestinal epithelium is compromised allowing for luminal bacterial lipopolysaccharide (LPS) endotoxin to infiltrate the host's bloodstream resulting in acute or chronic systemic stimulation of the innate immune system. Repeated exposure to LPS over a short period of time is reported to induce immunotolerance within the host. This LPS tolerance is an essential immunohomeostatic response that can protect against over activation of the inflammatory response during subsequent exposure to LPS. In the present study, Holstein calves (n = 20) were initially stress challenged with either saline, or 100, 200 or 400 ng/kg of LPS administered intramuscular, and again re-challenged with 200 ng/kg of LPS 2-weeks later. Serum was collected every 2 hr for 6 hr to profile changes in circulatory stress biomarkers after the repeated LPS exposures. Heifers that were initially challenged with 100, 200 and 400 ng/kg of LPS demonstrated significantly attenuated cortisol responses in the second challenge (p < 0.01, 0.01 and 0.05, respectively), whereas control animals who previously received saline demonstrated a strong cortisol response at 2 hr after receiving 200 ng/kg of LPS (p < 0.05). The cytokine/chemokine (IL-6, CCL2, CCL3 and CCL4) responses were also attenuated during the LPS rechallenge (p < 0.05). Finally, microRNA expression profiles were determined to assess the epigenetic response to repeated LPS exposure. Interestingly, miR-31 and miR-223 were downregulated in response to the second LPS challenge. The present study demonstrates the dynamic nature of the stress response in dairy cattle as it relates to the development of LPS tolerance. Understanding the roles of various stress biomarkers in the context of innate immune cell tolerance is essential for evaluating their impact on immune system homeostasis.

Keywords: Biomarkers; Dairy heifers; LPS Tolerance; Lipopolysaccharide; Stress

DOI: https://doi.org/10.1016/j.vetimm.2023.110579

Front Immunol. 2023 ;14 1083339

Megakaryocytes respond during sepsis and display innate immune cell behaviors.

Galit H Frydman, Felix Ellett, Julianne Jorgensen, Anika L Marand, Lawrence Zukerberg, Martin K Selig, Shannon N Tessier, Keith H K Wong, David Olaleye, Charles R Vanderburg, James G Fox, Ronald G Tompkins, Daniel Irimia.

Megakaryocytes (MKs) are precursors to platelets, the second most abundant cells in the peripheral circulation. However, while platelets are known to participate in immune responses and play significant functions during infections, the role of MKs within the immune system remains largely unexplored. Histological studies of sepsis patients identified increased nucleated CD61+ cells (MKs) in the lungs, and CD61+ staining (likely platelets within microthrombi) in the kidneys, which correlated with the development of organ dysfunction. Detailed imaging cytometry of peripheral blood from patients with sepsis found significantly higher MK counts, which we predict would likely be misclassified by automated hematology analyzers as leukocytes. Utilizing in vitro techniques, we show that both stem cell derived MKs (SC MKs) and cells from the human megakaryoblastic leukemia cell line, Meg-01, undergo chemotaxis, interact with bacteria, and are capable of releasing chromatin webs in response to various pathogenic stimuli. Together, our observations suggest that MK cells display some basic innate immune cell behaviors and may actively respond and play functional roles in the pathophysiology of sepsis.

Keywords: infectious; innate; megakaryocyte; platelet; sepsis

DOI: https://doi.org/10.3389/fimmu.2023.1083339