Publications

Aging increases susceptibility to a wide range of diseases, partially due to alterations in T lymphocytes. This study aimed to characterize age-related changes in T-cell output, phenotype, and function under basal conditions and after myocardial infarction (MI). Compared with young mice (2–6 mo), aged mice (≥18 mo) demonstrated reduced thymic size and fewer developing thymocytes. Accordingly, circulating T-cell counts were significantly lower in aged mice than in young mice. Interestingly, the spleen and bone marrow of aged mice showed increased T-cell accumulation, primarily due to expansion of memory T cells. Similarly, older humans (≥60 yr old) exhibited reduced circulating T cells and a higher proportion of memory T cells. Under basal conditions, aged splenic T cells expressed higher mRNA levels of proinflammatory and cytotoxic factors (e.g., Ifnγ, Tnfα, granzyme b, and perforin). Moreover, aged T cells exhibited a higher frequency of PD-1⁺, TIGIT⁺, LAG-3⁺, and CTLA-4⁺ cells compared with young T cells, indicative of an exhausted phenotype. Metabolically, aged T cells showed higher basal glycolytic and mitochondrial oxidative phosphorylation. Following MI, thymic regeneration was evident in young mice by day 14, whereas the aged thymus remained atrophic. In addition, aged MI mice exhibited reduced naïve T cells and increased memory T cells in the spleen and bone marrow compared with young mice. In conclusion, our study reveals that aging diminishes thymocyte output and circulating T-cell pools, facilitates memory T-cell accumulation, and compromises thymic regeneration under basal conditions and post-MI.

The thymus, where T lymphocytes develop and mature, is sensitive to insults such as tissue ischemia or injury. The insults can cause thymic atrophy and compromise T-cell development, potentially impairing adaptive immunity. The objective of this study was to investigate whether myocardial infarction (MI) induces thymic injury to impair T lymphopoiesis and to uncover the underlying mechanisms. When compared with sham controls, MI mice at day 7 post-MI exhibited smaller thymus, lower cellularity, as well as less thymocytes at different developmental stages, indicative of T-lymphopoiesis impairment following MI. Accordingly, the spleen of MI mice has less T cells and recent thymic emigrants (RTEs), implying that the thymus of MI mice releases fewer mature thymocytes than sham controls. Interestingly, the secretory function of splenic T cells was not affected by MI. Further experiments showed that the reduction of thymocytes in MI mice was due to increased thymocyte apoptosis. Removal of adrenal glands by adrenalectomy (ADX) prevented MI-induced thymic injury and dysfunction, whereas corticosterone supplementation in ADX + MI mice reinduced thymic injury and dysfunction, indicating that glucocorticoids mediate thymic damage triggered by MI. Eosinophils play essential roles in thymic regeneration postirradiation, and eosinophil-deficient mice exhibit impaired thymic recovery after sublethal irradiation. Interestingly, the thymus was fully regenerated in both wild-type and eosinophil-deficient mice at day 14 post-MI, suggesting that eosinophils are not critical for thymus regeneration post-MI. In conclusion, our study demonstrates that MI-induced glucocorticoids trigger thymocyte apoptosis and impair T lymphopoiesis, resulting in less mature thymocyte release to the spleen.

The phagocytosis and clearance of dying cells by macrophages, a process termed efferocytosis, is essential for both maintaining homeostasis and promoting tissue repair after infection or sterile injury. If not removed in a timely manner, uncleared cells can undergo secondary necrosis, and necrotic cells lose membrane integrity, release toxic intracellular components, and potentially induce inflammation or autoimmune diseases. Efferocytosis also initiates the repair process by producing a wide range of pro-reparative factors. Accumulating evidence has revealed that macrophage efferocytosis defects are involved in the development and progression of a variety of inflammatory and autoimmune diseases. The underlying mechanisms of efferocytosis impairment are complex, disease-dependent, and incompletely understood. In this review, we will first summarize the current knowledge about the normal signaling and metabolic processes of macrophage efferocytosis and its importance in maintaining tissue homeostasis and repair. We then will focus on analyzing the molecular and cellular mechanisms underlying efferocytotic abnormality (impairment) in disease or injury conditions. Next, we will discuss the potential molecular targets for enhanced efferocytosis in animal models of disease. To provide a balanced view, we will also discuss some deleterious effects of efferocytosis.

Some patients with myocardial infarction (MI) exhibit lymphopenia, a reduction in blood lymphocyte count. Moreover, lymphopenia inversely correlates with patient prognosis. The objective of this study was to elucidate the underlying mechanisms that cause lymphopenia after MI. Multiparameter flow cytometric analysis demonstrated that MI induced profound B and T lymphopenia in a mouse model, peaking at day 1 post-MI. The finding that non-MI control and MI mice exhibited similar apoptotic rate for blood B and T lymphocytes argues against apoptosis being essential for MI-induced lymphopenia. Interestingly, the bone marrow in day 1 post-MI mice contained more B and T cells but showed less B- and T-cell proliferation compared with day 0 controls. This suggests that blood lymphocytes may travel to the bone marrow after MI. This was confirmed by adoptive transfer experiments demonstrating that MI caused the loss of transferred lymphocytes in the blood, but the accumulation of transferred lymphocytes in the bone marrow. To elucidate the underlying signaling pathways, β₂-adrenergic receptor or sphingosine-1-phosphate receptor type 1 (S1PR1) was pharmacologically blocked, respectively. β₂-receptor inhibition had no significant effect on blood lymphocyte count, whereas S1PR1 blockade aggravated lymphopenia in MI mice. Furthermore, we discovered that MI-induced glucocorticoid release triggered lymphopenia. This was supported by the findings that adrenalectomy (ADX) completely prevented mice from MI-induced lymphopenia, and supplementation with corticosterone in adrenalectomized MI mice reinduced lymphopenia. In conclusion, our study demonstrates that MI-associated lymphopenia involves lymphocyte redistribution from peripheral blood to the bone marrow, which is mediated by glucocorticoids.

Emerging evidence shows that after injury or infection, the mesenteric lymph acts as a conduit for gut-derived toxic factors to enter the blood circulation, causing systemic inflammation and acute lung injury. Neither the cellular and molecular identity of lymph factors nor their mechanisms of action have been well understood and thus have become a timely topic of investigation. This review will first provide a summary of background knowledge on gut barrier and mesenteric lymphatics, followed by a discussion focusing on the current understanding of potential injurious factors in the lymph and their mechanistic contributions to lung injury. We also examine lymph factors with antiinflammatory properties as well as the bidirectional nature of the gut-lung axis in inflammation.

Neutrophils are first-line responders of the innate immune system. Following myocardial infarction (MI), neutrophils are quickly recruited to the ischemic region, where they initiate the inflammatory response, aiming at cleaning up dead cell debris. However, excessive accumulation and/or delayed removal of neutrophils are deleterious. Neutrophils can promote myocardial injury by releasing reactive oxygen species, granular components, and pro-inflammatory mediators. More recent studies have revealed that neutrophils are able to form extracellular traps (NETs) and produce extracellular vesicles (EVs) to aggravate inflammation and cardiac injury. On the contrary, there is growing evidence showing that neutrophils also exert anti-inflammatory, pro-angiogenic, and pro-reparative effects, thus facilitating inflammation resolution and cardiac repair. In this review, we summarize the current knowledge on neutrophils' detrimental roles, highlighting the role of recently recognized NETs and EVs, followed by a discussion of their beneficial effects and molecular mechanisms in post-MI cardiac remodeling. In addition, emerging concepts about neutrophil diversity and their modulation of adaptive immunity are discussed.

Gut ischemia/reperfusion (I/R) injury is a common clinical problem associated with significant mortality and morbidities that result from systemic inflammation and remote organ dysfunction, typically acute lung injury. The mechanisms underlying the dissemination of gut-derived harmful mediators into the circulation are poorly understood. The objective of our study was to determine the role of mesenteric lymphatic circulation in the systemic and pulmonary inflammatory response to gut I/R. Using a murine intestinal I/R model, we evaluated whether and how blocking mesenteric lymph flow affects the inflammatory response in local tissues (gut) and remote organs (lungs). We further explored the mechanisms of post-I/R lymph-induced systemic inflammation by examining neutrophil activity and interaction with endothelial cells in vitro. Mice subjected to intestinal I/R displayed a significant inflammatory response in local tissues, evidenced by neutrophil infiltration into mucosal areas, as well as lung inflammation, evidenced by increased myeloperoxidase levels, neutrophil infiltration, and elevated microvascular permeability in the lungs. Mesenteric lymph duct ligation (MLDL) had no effect on gut injury per se, but effectively attenuated lung injury following gut I/R. Cell experiments showed that lymph fluid from post-I/R animals, but not pre-I/R, increased neutrophil surface CD11b expression and their ability to migrate across vascular endothelial monolayers. Moreover, post-I/R lymph upregulated neutrophil expression of pro-inflammatory cytokines and chemokines, which was mediated by a mechanism involving nuclear factor (NF)-κB signaling. Consistently, gut I/R activated NF-κB in lung neutrophils, which was alleviated by MLDL. In conclusion, all these data indicate that mesenteric lymph circulation contributes to neutrophil activation and lung inflammation following gut I/R injury partly through activating NF-κB.