Metabolic transformation of fat in obesity determines the inflammation resolving capacity of splenocardiac and cardiorenal networks in heart failure.

All fats are not created equal, and despite the extensive literature, the effect of fat intake is the most debated question in obesity, cardiovascular, and cardiorenal research. Cellular and molecular mechanisms underlying cardiac dysfunction and consequent heart failure in the setting of obesity are not well understood. Our understanding of how fats are metabolically transformed after nonreperfused myocardial infarction (MI), in particular, is incomplete. Here, using male C57BL/6J mice (2 mo old), we determined the role of omega-6 fatty acids, provided as safflower oil (SO) for 12 wk, followed by supplementation with docosahexaenoic acid (DHA; n-3 fatty acids) for 8 wk before MI. With SO feeding, inflammation resolution was impaired. Specialized proresolving mediators (SPMs) increased in DHA-fed mice to reverse the effects of SO, whereas prostaglandins and thromboxane B2 were reduced in the spleen and amplified multiple resolving mechanisms in heart and kidney post-MI. DHA amplified the number of resolving macrophages and cardiac reparative pathways of the splenocardiac and cardiorenal networks in acute heart failure, with higher Treg cells in chronic heart failure and marked expression of Foxp3+ in the myocardium. Our findings indicate that surplus ingestion of SO intensified systemic, baseline, nonresolving inflammation, and DHA intake dominates splenocardiac resolving phase with the biosynthesis of SPMs and controlled cardiorenal inflammation in heart failure survivor mice.NEW & NOTEWORTHY Chronic and surplus dietary intake of safflower oil (SO) increased plasma creatinine dysregulated post-MI splenocardiac inflammation coincides with the dysfunctional cardiorenal network. In contrast, docosahexaenoic acid (DHA) increases post-MI survival in chronic heart failure. DHA transforms into specialized proresolving mediators (SPMs) and limited proinflammatory prostaglandins and thromboxanes following myocardial infarction (MI). DHA promotes Ly6Clow resolving macrophages and T regulatory cells (Foxp3+) in a splenocardiac manner post-MI.

Lack of resolution sensor drives age-related cardiometabolic and cardiorenal defects and impedes inflammation-resolution in heart failure.

OBJECTIVE: Recently, we observed that the specialized proresolving mediator (SPM) entity resolvin D1 activates lipoxin A4/formyl peptide receptor 2 (ALX/FPR2), which facilitates cardiac healing and persistent inflammation is a hallmark of impaired cardiac repair in aging. Splenic leukocyte-directed SPMs are essential for the safe clearance of inflammation and cardiac repair after injury; however, the target of SPMs remains undefined in cardiac healing and repair. METHODS: To define the mechanistic basis of ALX/FPR2 as a resolvin D1 target, ALX/FPR2-null mice were examined extensively. The systolic-diastolic heart function was assessed using echocardiography, leukocytes were phenotyped using flow cytometry, and SPMs were quantitated using mass spectrometry. The presence of cardiorenal syndrome was validated using histology and renal markers. RESULTS: Lack of ALX/FPR2 led to the development of spontaneous obesity and diastolic dysfunction with reduced survival with aging. After cardiac injury, ALX/FPR2-/- mice showed lower expression of lipoxygenases (-5, -12, -15) and a reduction in SPMs in the infarcted left ventricle and spleen, indicating nonresolving inflammation. Reduced SPM levels in the infarcted heart and spleen are suggestive of impaired cross-talk between the injured heart and splenic leukocytes, which are required for the resolution of inflammation. In contrast, cyclooxygenases (-1 and -2) were over amplified in the infarcted heart. Together, these results suggest interorgan signaling in which the spleen acts as both an SPM biosynthesizer and supplier in acute heart failure. ALX/FPR2 dysfunction magnified obesogenic cardiomyopathy and renal inflammation (↑NGAL, ↑TNF-α, ↑CCL2, ↑IL-1ß) with elevated plasma creatinine levels in aging mice. At the cellular level, ALX/FPR2-/- mice showed impairment of macrophage phagocytic function ex-vivo with expansion of neutrophils after myocardial infarction. CONCLUSIONS: Lack of ALX/FPR2 induced obesity, reduced the life span, amplified leukocyte dysfunction, and facilitated profound interorgan nonresolving inflammation. Our study shows the integrative and indispensable role of ALX/FPR2 in lipid metabolism, cardiac inflammation-resolution processes, obesogenic aging, and renal homeostasis.

Obesogenic diet in aging mice disrupts gut microbe composition and alters neutrophil:lymphocyte ratio, leading to inflamed milieu in acute heart failure.

Calorie-dense obesogenic diet (OBD) is a prime risk factor for cardiovascular disease in aging. However, increasing age coupled with changes in the diet can affect the interaction of intestinal microbiota influencing the immune system, which can lead to chronic inflammation. How age and calorie-enriched OBD interact with microbial flora and impact leukocyte profiling is currently under investigated. Here, we tested the interorgan hypothesis to determine whether OBD in young and aging mice alters the gut microbe composition and the splenic leukocyte profile in acute heart failure (HF). Young (2-mo-old) and aging (18-mo-old) mice were supplemented with standard diet (STD, ∼4% safflower oil diet) and OBD (10% safflower oil) for 2 mo and then subjected to coronary artery ligation to induce myocardial infarction. Fecal samples were collected pre- and post-diet intervention, and the microbial flora were analyzed using 16S variable region 4 rRNA gene DNA sequencing and Quantitative Insights Into Microbial Ecology informatics. The STD and OBD in aging mice resulted in an expansion of the genus Allobaculum in the fecal microbiota. However, we found a pathologic change in the neutrophil:lymphocyte ratio in aging mice in comparison with their young counterparts. Thus, calorie-enriched OBD dysregulated splenic leukocytes by decreasing immune-responsive F4/80+ and CD169+ macrophages in aging mice. OBD programmed neutrophil swarming with an increase in isoprostanoid levels, with dysregulation of lipoxygenases, cytokines, and metabolite-sensing receptor expression. In summary, calorie-dense OBD in aging mice disrupted the composition of the gut microbiome, which correlates with the development of integrative and system-wide nonresolving inflammation in acute HF.-Kain, V., Van Der Pol, W., Mariappan, N., Ahmad, A., Eipers, P., Gibson, D. L., Gladine, C., Vigor, C., Durand, T., Morrow, C., Halade, G. V. Obesogenic diet in aging mice disrupts gut microbe composition and alters neutrophil:lymphocyte ratio, leading to inflamed milieu in acute heart failure.

Epigenetics of chronic inflammatory diseases.

Chronic, noncommunicable, and inflammation-associated diseases remain the largest cause of morbidity and mortality globally and within the United States. This is mainly due to our limited understanding of the molecular mechanisms that underlie these complex pathologies. The available evidence indicates that studies of epigenetics (traditionally defined as the heritable changes to gene expression that are independent of changes to DNA) are significantly advancing our knowledge of these inflammatory conditions. This review will focus on epigenetic studies of three diseases, that are among the most burdensome globally: cardiovascular disease, the number one cause of deaths worldwide, type 2 diabetes and, Alzheimer's disease. The current status of epigenetic research, including the ability to predict disease risk, and key pathophysiological defects are discussed. The significance of defining the contribution of epigenetic defects to nonresolving inflammation and aging, each associated with these diseases, is highlighted, as these are likely to provide new insights into inflammatory disease pathogenesis.

Inflammatory cells infiltration status in bladder submucosa of patients with cystitis glandularis and its clinical significance / 中华泌尿外科杂志

Objective To analyze the infiltration of inflammatory cells under the mucosa of female cystitis glandularis and the different inflammatory infiltration in different clinical pathological types of cystitis glandularis.Methods Immunohistochemical method was used to detect the bladder mucosal tissue samples of 10 female patients confirmed cystitis glandularis admitted from June 2016 to October 2016.The results of immunohistochemical staining were collected and statistically analyzed by the automatic microscopy and image analysis system.In addition,the clinical data and tissue sample of 49 cases of cystitis glandularis treated from December 2006 to August 2017 were collected.Age of 49 patients was (34.4 ±7.5) years old and BMI was (21.9 ± 4.2) kg/m2.There were 19 cases of hypertension and 18 cases of diabetes.According to the cystoscopic manifestations,follicular edema type,papilloma type,and intestinal adenomatosis type were defined as high risk.Chronic inflammatory type and mucosa unchanged type were defined as low risk.Immunohistochemical staining was used to detect tissue samples,to compare the general data of different types of cystitis glandularis and the degree of infiltration of bladder mucosal inflammatory cells.Results T lymphocytes were highly expressed in 10 patients,and B lymphocytes and plasma cells were not expressed or extremely low (P ＜ 0.01).Of the 49 patients,29 were high risk type cystitis glandularis (follicular edema type,papilloma type,and intestinal adenomatosis type),and 21 were low risk type (chronic inflammatory type and mucosa unchanged type).The age of the high-risk group was (34.4 ± 7.5) years old with BMI of (21.9 ±4.2) kg/m2,8 cases of hypertension and 8 cases of diabetes.The age of the low-risk group was (38.2 ±8.5) years old with BMI of (20.8 ±4.0) kg/m2,11 cases of hypertension and 10 cases of diabetes.There was no statistically significant difference between two groups (P ＞ 0.05).The OABSS of high-risk group(10.4 ± 2.6) was significantly higher than that of low-risk group (7.1 ± 2.1,P ＜ 0.01).QOL of high-risk group (4.9 ± 0.9) was significantly higher than that of low-risk group (4.1 ± 0.8,P ＜ 0.01).Qmax of high-risk group was (11.4 ± 3.6) ml/s,significantly lower than that of low-risk group[(15.8 ±3.8) ml/s,P ＜0.01].The positive number of T lymphocytes of high-risk group was (173.5 ± 26.8),which was significantly higher than that of low-risk group(119.5 ± 21.2,P ＜ 0.01).Conclusions T lymphocytes infiltration is the major phenomenon in bladder submucosa of female patients with cystitis glandularis.The inflammatory infiltration by T lymphocytes could be associated with patient's symptom and bladder's pathological changes.

Macrophage Polarization.

Macrophage polarization refers to how macrophages have been activated at a given point in space and time. Polarization is not fixed, as macrophages are sufficiently plastic to integrate multiple signals, such as those from microbes, damaged tissues, and the normal tissue environment. Three broad pathways control polarization: epigenetic and cell survival pathways that prolong or shorten macrophage development and viability, the tissue microenvironment, and extrinsic factors, such as microbial products and cytokines released in inflammation. A plethora of advances have provided a framework for rationally purifying, describing, and manipulating macrophage polarization. Here, I assess the current state of knowledge about macrophage polarization and enumerate the major questions about how activated macrophages regulate the physiology of normal and damaged tissues.

Study of the relationships between myeloid-derived suppressor cells (MDSC) and nonresolving inflammation (NRI) in tumor microenvironment / 中华微生物学和免疫学杂志

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immunosuppressive cells derived from bone marrow stem cells.MDSCs can not only strongly inhibit the anti-tumor immune reactions mediated by T cells,but also directly accelerate angiogenesis,tumor progression and metastasis.Nonresolving inflammation (NRI),a major driving factor in the occurrence and development of tumor,and MDSCs are present in tumor microenvironment and become hot topics in recent years.However,the relationships between MDSCs and NRI,especially in the relevant molecular regulatory networks,have not been fully elucidated.The relationships between MDSCs and NRI,the molecular regulatory networks,the key regulatory points and the strategies for targeted treatment are reviewed in this paper based on the current literatures and the work achieved by our research team.

The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes.

Hypoxic pulmonary hypertension (PH) comprises a heterogeneous group of diseases sharing the common feature of chronic hypoxia-induced pulmonary vascular remodeling. The disease is usually characterized by mild to moderate pulmonary vascular remodeling that is largely thought to be reversible compared with the progressive irreversible disease seen in World Health Organization (WHO) group I disease. However, in these patients, the presence of PH significantly worsens morbidity and mortality. In addition, a small subset of patients with hypoxic PH develop "out-of-proportion" severe pulmonary hypertension characterized by pulmonary vascular remodeling that is irreversible and similar to that in WHO group I disease. In all cases of hypoxia-related vascular remodeling and PH, inflammation, particularly persistent inflammation, is thought to play a role. This review focuses on the effects of hypoxia on pulmonary vascular cells and the signaling pathways involved in the initiation and perpetuation of vascular inflammation, especially as they relate to vascular remodeling and transition to chronic irreversible PH. We hypothesize that the combination of hypoxia and local tissue factors/cytokines ("second hit") antagonizes tissue homeostatic cellular interactions between mesenchymal cells (fibroblasts and/or smooth muscle cells) and macrophages and arrests these cells in an epigenetically locked and permanently activated proremodeling and proinflammatory phenotype. This aberrant cellular cross-talk between mesenchymal cells and macrophages promotes transition to chronic nonresolving inflammation and vascular remodeling, perpetuating PH. A better understanding of these signaling pathways may lead to the development of specific therapeutic targets, as none are currently available for WHO group III disease.

Diabetic retinopathy: a nonresolving inflammation / 中华实验眼科杂志

Nonresolving inflammation plays an important role in the onset and development of various diseases.Diabetic retinopathy (DR) is a low-degree chronic inflammatory process,and actually it would be a nonresolving inflammatory disease.Failure of neutrophils apoptosis in time,converting failure of macrophages from a pro-inflammatory to anti-inflammatory phenotype,dysfunction of pericytes and poor activation of Thl cells are all contributed to inflammatory prolong.Meanwhile the low concentration of anti-inflammatory soluble factors such as interleukin-10 (IL-10),transforming growth factor-β (TGF-β),nitric oxide (NO),epoxyeicosatrienoic acids (EETs)and lipoxins in serum or ocular specimen are also benefit to failure of inflammatory resolution.In addition,persistent stimulation such as lipid products,advanced glycation end products(AGEs) and reactive oxygen intermediate (ROI)deteriorate the inflammation persistently.More understanding of DR pathogenesis greatly complicates the development of anti-inflammatory therapy.