Lipocalin-2 promotes adipose-macrophage interactions to shape peripheral and central inflammatory responses in experimental autoimmune encephalomyelitis

Objective: Accumulating evidence suggests that dysfunctional adipose tissue (AT) plays a major role in the risk of developing multiple sclerosis (MS), the most common immune-mediated and demyelinating disease of the central nervous system. However, the contribution of adipose tissue to the etiology and progression of MS is still obscure. This study aimed at deciphering the responses of AT in experimental autoimmune encephalomyelitis (EAE), the best characterized animal model of MS. Results and methods: We observed a significant AT loss in EAE mice at the onset of disease, with a significant infiltration of M1-like macrophages and fibrosis in the AT, resembling a cachectic phenotype. Through an integrative and multilayered approach, we identified lipocalin2 (LCN2) as the key molecule released by dysfunctional adipocytes through redox-dependent mechanism. Adipose-derived LCN2 shapes the pro-inflammatory macrophage phenotype, and the genetic deficiency of LCN2 specifically in AT reduced weight loss as well as inflammatory macrophage infiltration in spinal cord in EAE mice. Mature adipocytes downregulating LCN2 reduced lipolytic response to inflammatory stimuli (e.g. TNFα) through an ATGL-mediated mechanism. Conclusions: Overall data highlighted a role LCN2 in exacerbating inflammatory phenotype in EAE model, suggesting a pathogenic role of dysfunctional AT in MS

No difference in return to amateur sports after medial and lateral unicompartmental knee arthroplasty in patients younger than 65 years

Purpose: The aim of this study was to assess the return to amateur sports of patients under 65 years, following medial unicompartmental knee arthroplasty (mUKA) versus lateral unicompartmental knee arthroplasty (lUKA). It was hypothesized that patients younger than 65 years who underwent lateral or medial unicondylar knee replacement will result in similar rates to amateur sports, at a minimum follow-up of 2 years. Method: Patients who underwent medial or lateral UKA participated in a 2-year follow-up program, where they were clinically evaluated for their return to amateur sports, using the University of California, Los Angeles (UCLA) activity scale and the High-Activity Arthroplasty Score (HAAS). Furthermore, subgroup analyses by gender and age were performed. Power analysis was performed to ensure sample size considering that lUKA is implanted ten times less frequently than its medial counterpart. Results: There were 85 patients who completed the entire minimum 2-year follow-up of which 73 belonged to the mUKA group and 12 to the lUKA group. No preoperative differences were found between the groups regarding the gender, the affected side, age, and mean follow-up. Both groups showed statistically significant improvement (p < 0.05) in their return to amateur sports in all parameters (UCLA and HAAS). No differences among the two groups were found at T 0 and T 1 (n.s.) . All subgroups showed a statistically significant improvement (p < 0.05) with respect to the preoperative value, except for UCLA for lUKA with less than 60 years and HAAS for males in the lUKA group (n.s.). No differences were found among subgroups both at T o and T 1 (n.s.). Conclusion: Both mUKA and lUKA procedures enabled all young and active patients a certain return to amateur sports 2 years after surgery, regardless of age and gender. UKA, medial or lateral, should always be considered for the treatment of isolated osteoarthritis in young and active patients with high functional demands. Level of evidence: Cohort Study, Level of Evidence III. Registration: Researchregistry6221 – Research Registry www.researchregistry.com

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field