Chronic inflammation in visceral adipose tissue (VAT) precipitates the development of cardiometabolic disorders. Although changes in T cell function associated with visceral obesity are thought to affect chronic VAT inflammation, the specific features of these changes remain elusive. Here, we have determined that a high-fat diet (HFD) caused a preferential increase and accumulation of CD44^hiCD62L^loCD4⁺ T cells that constitutively express PD-1 and CD153 in a B cell–dependent manner in VAT. These cells possessed characteristics of cellular senescence and showed a strong activation of Spp1 (encoding osteopontin [OPN]) in VAT. Upon T cell receptor stimulation, these T cells also produced large amounts of OPN in a PD-1–resistant manner in vitro. The features of CD153⁺PD-1⁺CD44^hiCD4⁺ T cells were highly reminiscent of senescence-associated CD4⁺ T cells that normally increase with age. Adoptive transfer of CD153⁺PD-1⁺CD44^hiCD4⁺ T cells from HFD-fed WT, but not Spp1-deficient, mice into the VAT of lean mice fed a normal diet recapitulated the essential features of VAT inflammation and insulin resistance. Our results demonstrate that a distinct CD153⁺PD-1⁺CD44^hiCD4⁺ T cell population that accumulates in the VAT of HFD-fed obese mice causes VAT inflammation by producing large amounts of OPN. This finding suggests a link between visceral adiposity and immune aging.

Background: Both osteopontin (OPN) and galectin-3 have been implicated in phagocytic clearance of dead cells and reparative fibrosis during wound healing. CD206 ⁺ macrophages are involved in tissue repair through phagocytosis and fibrosis after myocardial infarction (MI). However, the relationship among OPN, galectin-3, and macrophage polarization in the context of MI remains unclear. Methods: The time course of Spp1 (encoding OPN) expression in the heart after MI showed a strong activation of Spp1 on day 3 after MI. To identify where in the body and in which cells the transcriptional activity of Spp1 increased after MI, we analyzed EGFP (enhanced green fluorescent protein)- Spp1 knockin reporter mice on day 3 after MI. Results: The transcriptional activity of Spp1 increased only in CD206 ⁺ macrophages in the infarct myocardium, and most of CD206 ⁺ macrophages have strong transcriptional activation of Spp1 after MI. The temporal expression pattern of Lgal3 (encoding galectin-3) in cardiac macrophages after MI was similar to that of Spp1 , and OPN is almost exclusively produced by galectin-3 ^hi CD206 ⁺ macrophages. Although both interleukin (IL)–4 and IL-10 were reported to promote CD206 ⁺ macrophage-mediated cardiac repair after MI, IL-10– but not IL-4–stimulated CD11b ⁺ Ly6G ⁻ cells could differentiate into OPN-producing galectin-3 ^hi CD206 ⁺ macrophages and showed enhanced phagocytic ability. Inhibition of STAT3 tyrosine phosphorylation suppressed IL-10–induced expression of intracellular galectin-3 and transcriptional activation of Spp1. Knockdown of galectin-3 suppressed their ability to differentiate into OPN-producing cells, but not STAT3 activation. The tyrosine phosphorylation of STAT3 and the appearance rate of galectin-3 ^hi CD206 ⁺ cells on cardiac CD11b ⁺ Ly6G ⁻ cells in Spp1 knockout mice were the same as those in wild-type mice. Spp1 knockout mice showed vulnerability to developing post-MI left ventricular chamber dilatation and the terminal deoxynucleo-tidyltransferase 2‘-Deoxyuridine-5‘-triphosphate nick-end labeling (TUNEL)–positive cells in the infarcted myocardium after MI remained higher in number in Spp1 knockout mice than in wild-type mice. Conclusions: OPN is almost exclusively produced by galectin-3 ^hi CD206 ⁺ macrophages, which specifically appear in the infarct myocardium after MI. The IL-10–STAT3–galectin-3 axis is essential for OPN-producing reparative macrophage polarization after myocardial infarction, and these macrophages contribute to tissue repair by promoting fibrosis and clearance of apoptotic cells. These results suggest that galectin-3 may contribute to reparative fibrosis in the infarct myocardium by controlling OPN levels.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been attracting attention for cardiovascular as well as antidiabetic effects since the results of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME Trial) were reported. The hematocrit increases during treatment with SGLT2 inhibitors, which have a diuretic effect but do not cause sufficient hemoconcentration to increase the risk of cerebral infarction. Elevation of the hematocrit during SGLT2 inhibitor therapy is presumed to involve enhancement of erythropoiesis in addition to hemoconcentration. In patients with diabetes, the erythropoietin level increases after initiation of treatment with the SGLT2 inhibitor dapagliflozin and reaches a plateau in 2 - 4 weeks. The reticulocyte count increases simultaneously, followed by elevation of hemoglobin and hematocrit. In patients with diabetes, the proximal tubules are overtaxed by excessive glucose reabsorption and the increased oxygen requirement causes tubulointerstitial hypoxia. Consequently, erythropoietin production is impaired because "neural crest-derived" fibroblasts surrounding the damaged renal tubules undergo transformation into dysfunctional fibroblasts. SGLT2 inhibitors reduce the workload of the proximal tubules and improve tubulointerstitial hypoxia, allowing fibroblasts to resume normal erythropoietin production. These drugs represent a new class of diuretics that have a renoprotective effect by improving tubulointerstitial hypoxia, which is the final common pathway to end-stage renal disease. In patients with diabetes, elevation of hematocrit may be a surrogate marker for recovery from reversible tubulointerstitial injury.

Rationale:: In-hospital outcomes are generally acceptable in patients with type B dissection; however, some patients present with undesirable complications, such as aortic expansion and rupture. Excessive inflammation is an independent predictor of adverse clinical outcomes. Objective:: We have investigated the underlying mechanisms of catastrophic complications after acute aortic dissection (AAD) in mice. Methods and Results:: When angiotensin II was administered in lysyl oxidase inhibitor–preconditioned mice, AAD emerged within 24 hours. The dissection was initiated at the proximal site of the descending thoracic aorta and propagated distally into an abdominal site. Dissection of the aorta caused dilatation, and ≈70% of the mice died of aortic rupture. AAD triggered CXCL1 and granulocyte-colony stimulating factor expression in the tunica adventitia of the dissected aorta, leading to elevation of circulating CXCL1/granulocyte-colony stimulating factor levels. Bone marrow CXCL12 was reduced. These chemokine changes facilitated neutrophil egress from bone marrow and infiltration into the aortic adventitia. Interference of CXCL1 function using an anti-CXCR2 antibody reduced neutrophil accumulation and limited aortic rupture post AAD. The tunica adventitia of the expanded dissected aorta demonstrated high levels of interleukin-6 (IL-6) expression. Neutrophils were the major sources of IL-6, and CXCR2 neutralization significantly reduced local and systemic levels of IL-6. Furthermore, disruption of IL-6 effectively suppressed dilatation and rupture of the dissected aorta without any influence on the incidence of AAD and neutrophil mobilization. Conclusions:: Adventitial CXCL1/granulocyte-colony stimulating factor expression in response to AAD triggers local neutrophil recruitment and activation. This leads to adventitial inflammation via IL-6 and results in aortic expansion and rupture.

Background: Left ventricular ( LV ) remodeling leads to chronic heart failure and is a main determinant of morbidity and mortality after myocardial infarction ( MI ). At the present time, therapeutic options to prevent LV remodeling are limited. Methods and Results: We created a large MI by permanent ligation of the coronary artery and identified a potential link between the interleukin ( IL )–23/ IL ‐17A axis and γδ T cells that affects late‐stage LV remodeling after MI . Despite the finsinf that infarct size 24 hours after surgery was similar to that in wild‐type mice, a deficiency in IL ‐23, IL ‐17A, or γδ T cells improved survival after 7 days, limiting infarct expansion and fibrosis in noninfarcted myocardium and alleviating LV dilatation and systolic dysfunction on day 28 post‐ MI . M ₁ macrophages and neutrophils were the major cellular source of IL ‐23, whereas >90% of IL ‐17A‐producing T cells in infarcted heart were CD 4 ⁻ TCR γδ ⁺ (γδ T ) cells. Toll‐like receptor signaling and IL ‐1β worked in concert with IL ‐23 to drive expansion and IL ‐17A production in cardiac γδ T cells, whereas the sphingosine‐1‐phosphate receptor and CCL 20/ CCR 6 signaling pathways mediated γδ T cell recruitment into infarcted heart. IL ‐17A was not involved in the acute inflammatory response, but it functioned specifically in the late remodeling stages by promoting sustained infiltration of neutrophils and macrophages, stimulating macrophages to produce proinflammatory cytokines, aggravating cardiomyocyte death, and enhancing fibroblast proliferation and profibrotic gene expression. Conclusions: The IL ‐23/ IL ‐17A immune axis and γδ T cells are potentially promising therapeutic targets after MI to prevent progression to end‐stage dilated cardiomyopathy.

Even in the presence of excess glucose, the proximal renal tubules continue to resorb more glucose. Sodium glucose cotransporter 2 (SGLT2) inhibitors are drugs that control this "greed" (H. Ito, Keio University, Japan). Negative feedback mechanisms maintain homeostasis for various physiological functions. However, there is no negative feedback mechanism for resorption of glucose by the proximal renal tubules. When food was scarce during human evolution, not limiting nutrient reabsorption was advantageous for survival, but the opposite is true in the era of satiation. SGLT2 inhibitors were designed to apply the brakes to uncontrolled glucose resorption by the kidneys in patients with diabetes. It has become clear that SGLT2 inhibitors not only improve the blood glucose level, but also show cardiovascular and renal protective effects irrespective of the reduction of blood glucose in patients with type 2 diabetes mellitus (T2DM). The mechanisms underlying cardiovascular and renal protection by SGLT2 inhibitors in T2DM are complex, multifactorial, and not completely understood. A common, and perhaps underappreciated, feature of T2DM is chronic activation of the sympathetic nervous system. This elevation of sympathetic activity contributes to the development of hypertension. It is also associated with a poor prognosis and with increased cardiovascular and renal morbidity/mortality independently of the effect on blood pressure. This review discusses novel insights into cardiovascular protection by SGLT2 inhibitors, focusing on the interaction between SGLT2 and the sympathetic nervous system.