The tissue microenvironment contributes to local immunity and to the pathogenesis of autoimmune diseases - a diverse set of conditions characterized by sterile inflammation, immunity against self-antigens, and destruction of tissues. However, the specific factors within the tissue microenvironment that contribute to local immune dysregulation in autoimmunity are poorly understood. One particular tissue component implicated in multiple autoimmune diseases is hyaluronan (HA), an extracellular matrix (ECM) polymer. HA is abundant in settings of chronic inflammation and contributes to lymphocyte activation, polarization, and migration. Here, we first describe what is known about the size, amount, and distribution of HA at sites of autoimmunity and in associated lymphoid structures in type 1 diabetes, multiple sclerosis, and rheumatoid arthritis. Next, we examine the recent literature on HA and its impact on adaptive immunity, particularly in regards to the biology of lymphocytes and Foxp3+ regulatory T-cells (Treg), a T-cell subset that maintains immune tolerance in healthy individuals. We propose that HA accumulation at sites of chronic inflammation creates a permissive environment for autoimmunity, characterized by CD44-mediated inhibition of Treg expansion. Finally, we address potential tools and strategies for targeting HA and its receptor CD44 in chronic inflammation and autoimmunity.

Despite antibiotics and sterile technique, postoperative infections remain a real and present danger to patients. Recent estimates suggest that 50% of the pathogens associated with postoperative infections have become resistant to the standard antibiotics used for prophylaxis. Risk factors identified in such cases include obesity and antibiotic exposure. To study the combined effect of obesity and antibiotic exposure on postoperative infection, mice were allowed to gain weight on an obesogenic Western-type diet (WD), administered antibiotics and then subjected to an otherwise recoverable sterile surgical injury (30% hepatectomy). The feeding of a WD alone resulted in a major imbalance of the cecal microbiota characterized by a decrease in diversity, loss of Bacteroidetes, a bloom in Proteobacteria, and the emergence of antibiotic-resistant organisms among the cecal microbiota. When WD-fed mice were administered antibiotics and subjected to 30% liver resection, lethal sepsis, characterized by multiple-organ damage, developed. Notable was the emergence and systemic dissemination of multidrug-resistant (MDR) pathobionts, including carbapenem-resistant, extended-spectrum β-lactamase-producing Serratia marcescens, which expressed a virulent and immunosuppressive phenotype. Analysis of the distribution of exact sequence variants belonging to the genus Serratia suggested that these strains originated from the cecal mucosa. No mortality or MDR pathogens were observed in identically treated mice fed a standard chow diet. Taken together, these results suggest that consumption of a Western diet and exposure to certain antibiotics may predispose to life-threating postoperative infection associated with MDR organisms present among the gut microbiota. IMPORTANCE Obesity remains a prevalent and independent risk factor for life-threatening infection following major surgery. Here, we demonstrate that when mice are fed an obesogenic Western diet (WD), they become susceptible to lethal sepsis with multiple organ damage after exposure to antibiotics and an otherwise-recoverable surgical injury. Analysis of the gut microbiota in this model demonstrates that WD alone leads to loss of Bacteroidetes, a bloom of Proteobacteria, and evidence of antibiotic resistance development even before antibiotics are administered. After antibiotics and surgery, lethal sepsis with organ damage developed in in mice fed a WD with the appearance of multidrug-resistant pathogens in the liver, spleen, and blood. The importance of these findings lies in exposing how the selective pressures of diet, antibiotic exposure, and surgical injury can converge on the microbiome, resulting in lethal sepsis and organ damage without the introduction of an exogenous pathogen.

Objective To compare outcomes of juvenile nasopharyngeal angiofibroma (JNA) resection between embolized and non‐embolized cohorts, and between transarterial embolization (TAE) and direct puncture embolization (DPE). Data Sources Per PRISMA guidelines, PubMed, Embase, Web of Science, Scopus, and Cochrane databases were searched for publications prior to or in 2021. Materials and Methods Original English manuscripts investigating the resection of JNA with and without preoperative embolization were included. Embolization type, recurrence rate, complication rates, blood loss, and transfusions were extracted. Risk of bias was assessed by the Risk of Bias in Non‐randomized Studies—of Interventions method. Results There were 61 studies with 917 patients included. Preoperative embolization was performed in 79.3% of patients. Of those embolized, 75.8% (N = 551) underwent TAE and 15.8% (N = 115) underwent DPE. JNA recurrence in embolized patients was lower than in non‐embolized patients (9.3% vs. 14.4%; odds ratio [OR]: 0.61, 95% confidence interval [CI]: 0.35, 1.06). DPE resulted in lower rates of disease recurrence (0% vs. 9.5%; OR: 0.066, 95% CI: 0.016, 0.272) and complications (1.8% vs. 21.9%; OR: 0.07, 95% CI: 0.02, 0.3) than TAE. A random effects Bayesian model was performed to analyze the difference in mean blood loss in 6 studies that included both embolized and non‐embolized patients. This analysis showed a mean reduction in blood loss of 798 mL in the embolized group. Conclusions We found embolization decreases blood loss in JNA resection. DPE led to improved recurrence and complication rates when compared to TAE, but future prospective studies are needed to further evaluate which embolization technique can optimize outcomes in JNA. Level of Evidence NA Laryngoscope, 133:1529–1539, 2023

The adipokine chemerin has been considered an important regulator of tumor immune surveillance. Chemerin recruits leukocytes through the receptor CMKLR1 to improve clinical outcomes of tumors and overall patient survival, but the role of GPR1 in tumors has not been widely investigated. Here, we found that GPR1 expression is elevated in breast cancerespecially triple-negative breast cancer (TNBC) tissues and cell lines. Herein, we screened a phage display peptide library to identify LRH7-G5, a peptide antagonist that blocks chemerin/GPR1 signaling. This peptide performed as an anticancer agent to suppress the proliferation of the TNBC cell lines MDA-MB-231 and HCC1937 but has little effect on T47D cells. LRH7-G5 treatment significantly blocked tumor growth in a TNBC cell-bearing orthotopic mouse model. Last, our results showed that this peptide's antitumor role is mediated through the PI3K/AKT signaling pathway. In conclusion, these data collectively suggest that the chemerin receptor GPR1 is a novel target for controlling TNBC progression and establish peptide LRH7-G5 as a new therapeutic agent for suppressing TNBC tumor growth.

Age related olfactory dysfunction, or presbyosmia, is a common sensory impairment in aging adults. People in this demographic group with comorbid conditions or exposure to viral, traumatic, or environmental insults remain at the greatest risk for impairment. Several methods for assessing olfaction exist, but they are only available in special settings and require consideration of age, sex, ancestry, and cognition. Perhaps most importantly, olfactory dysfunction has been suggested as an early sign of Alzheimer’s and Parkinson’s disease and therefore may serve as a tool in the diagnosis and prognosis of these neurodegenerative conditions. Outside of this context, olfactory loss also impacts nutrition, safety, and social relationships, and even predicts mortality itself. This review covers the detection and manifestations of olfactory decline in aging individuals and the myriad ways in which olfactory impairment is connected to their health and well-being.

Osteoprotegerin (OPG) is involved in various biological processes, including bone remodeling, vascular calcification and pancreatic β-cell function. Although some clinical studies have shown an increase in serum OPG level during pregnancy, the role of OPG in gestational diabetes mellitus (GDM) is largely unknown. Therefore, we explored the effect of OPG in metabolic homeostasis during pregnancy. We initially evaluated serum OPG levels using ELISA and western blotting techniques on samples from GDM patients. We also assessed OPG expression levels in maternal mice. We then used blastocysts transduced with lentiviruses capable of trophoblast-specific transgene expression to establish placenta-specific OPG knockdown or overexpression mouse models for functional and mechanistic investigation after embryo transplantation. We found that OPG expression was positively associated with GDM in clinical samples, and OPG levels were significantly increased in GDM patient sera and term placenta. Serum OPG was significantly increased in maternal compared to non-pregnant mice, and expression levels of OPG were the highest in placenta compared with other organs, including bone, liver and pancreas. OPG was also significantly increased in pregnant mice fed a high-fat diet (HFD). Placenta-specific OPG knockdown induced glucose intolerance, decreased β-cell proliferation and decreased serum insulin levels, whereas placenta-specific OPG overexpression promoted glucose tolerance and enhanced β-cell proliferation, which increased serum insulin production and decreased fetal weight in HFD-feeding pregnant mice. Placenta-derived OPG (pl-OPG) regulated glucose homeostasis during pregnancy via enhancement of β-cell proliferation, which suggests a potential therapeutic application of OPG for GDM.

Objectives: Determine whether preoperative dietary prehabilitation with a low-fat, high-fiber diet reverses the impact of Western diet (WD) on the intestinal microbiota and improves postoperative survival Background: We have previously demonstrated that WD fed mice subjected to an otherwise recoverable surgical injury (30% hepatectomy), antibiotics, and a short period of starvation demonstrate reduced survival (29%) compared to mice fed a low-fat, high-fiber standard chow (SD) (100%). Methods: Mice were subjected to 6 weeks of a WD and underwent dietary pre-habilitation (3 days vs 7 days) with a SD prior to exposure to antibiotics, starvation, and surgery. 16S rRNA gene sequencing was utilized to determine microbiota composition. Mass spectrometry measured short chain fatty acids and functional prediction from 16S gene amplicons were utilized to determine microbiota function. Results: As early as 24 hours, dietary prehabilitation of WD mice resulted in restoration of bacterial composition of the stool microbiota, transitioning from Firmicutes dominant to Bacteroidetes dominant. However, during this early pre-habilitation (ie, 3 days), stool butyrate per microbial biomass remained low and postoperative mortality remained unchanged from WD. Microbiota function demonstrated reduced butyrate contributing taxa as potentially responsible for failed recovery. In contrast, after 7 days of prehabilitation (7DP), there was greater restoration of butyrate producing taxa and survival after surgery improved (29% vs 79% vs 100%: WD vs 7DP vs SD, P < 0.001). Conclusions:The deleterious effects of WD on the gut microbiota can be restored after 7 days of dietary prehabilitation. Moreover, stool markers may define the readiness of the microbiome to withstand the process of surgery including exposure to antibiotics and short periods of starvation.

Expression of the transcription factor Interferon Regulatory Factor 4 (IRF4) is required for the development of lung conventional dendritic cells type 2 (cDC2s) that elicit Th2 responses, yet how IRF4 functions in lung cDC2s throughout the acute and memory allergic response is not clear. Here, we use a novel mouse model that loses IRF4 expression after lung cDC2 development to demonstrate that mice with IRF4-deficient DCs display impaired memory responses to allergen. This defect in the memory response is a direct result of ineffective Th2 induction and impaired recruitment of activated effector T cells to the lung after sensitization. IRF4-deficient DCs demonstrate defects in their migration to the draining lymph node and in T cell priming. Finally, T cells primed by IRF4-competent DCs mediate potent memory responses independently of IRF4-expressing DCs, demonstrating that IRF4-expressing DCs are not necessary during the memory response. Thus, IRF4 controls a program in mature DCs governing Th2 priming and effector responses, but IRF4-expressing DCs are dispensable during tissue resident-memory T cell (TRM cell)-dependent memory responses.