Tracing the failing heart: dual genetic fate mapping for target identification

In a recent study published in Nature Genetics,1 Han and colleagues employed a dual genetic lineage tracing approach in combination with a model of heart failure(HF)to identify a key sub-population of endocardium-derived fibroblasts,which gives rise to excessive myofibroblast formation in a Wnt pathway-mediated manner and contributes to cardiac fibrosis.1 The identified fibroblast sub-population and Wnt signaling pathway could be novel targets for the therapy of HF.Improvements in risk management and cardiovascular inter-vention have significantly reduced age-specific cardiovascular disease-related mortality.In contrast,the rate of HF-related hospitalisations has increased over the past decades and HF is a disease with highest social and economic cost in industrialized countries.HF is defined as impairment of the heart’s blood pumping function and its severity is assessed based on ejection fraction.HF often occurs after myocardial infarction(MI),with infarct size and quality of ventricular remodeling after MI influencing ventricular dysfunctions.Causes of HF also include hypertension,atrial fibrillation,and cardiomyopathies(Fig.1).Especially elderly patients with recurrent MI and comorbidities are increasingly presenting with signs of HF.

Breaking barriers:noncanonical inflammasome executes blood–brain barrier disruption

In a landmark study recently published in Nature,1 Wei and colleagues demonstrate that the activation of GSDMD by the cytosolic lipopolysaccharide(LPS)sensor caspase-11 triggers blood–brain barrier(BBB)breakdown upon LPS challenge independent of TLR4-induced cytokine release.Their work identifies the noncanonical inflammasome and GSDMD pore formation as a potential target for treating central nervous system(CNS)disorders associated with inflammatory BBB dysfunction.

IKKβ binds NLRP3 providing a shortcut to inflammasome activation for rapid immune responses

Dear Editor,A rapid immune response to signals released from pathogens and injuries is critical for maintaining tissue integrity and restoring homeostasis.This response is largely mediated by the concerted action of pattern recognition receptors(PRRs).Such cooperativity has been described for Toll-like receptors(TLRs)and NACHT,LRR,and pyrin domain-containing protein 3(NLRP3),but the underlying molecular mechanisms remain incompletely understood.Inflammasomes are multi-protein complexes defined by a cytosolic innate immune sensor,usually a PRR,which recruits the adaptor molecule apoptosis-associated speck-like protein containing a caspase-recruitment domain(ASC)to activate the effector caspase-1 leading to the release of matured IL-1βand IL-18.Active caspase-1 further cleaves gasdermin D(GSDMD)allowing the N-terminal domain of GSDMD(GSDMD-N)to form pores in the plasma membrane,thus facilitating the release of matured IL-1βand IL-18.Pore-forming GSDMD-N further induces pyroptosis,an inflammatory form of cell death.

Considerations on the role of environmental toxins in idiopathic Parkinson’s disease pathophysiology

Neurodegenerative diseases are characterized by a progressive dysfunction of the nervous system.Often associated with atrophy of the affected central or peripheral nervous structures,they include diseases such as Parkinson’s Disease(PD),Alzheimer’s Disease and other dementias,Genetic Brain Disorders,Amyotrophic Lateral Sclerosis(ALS or Lou Gehrig’s Disease),Huntington’s Disease,Prion Diseases,and others.The prevalence of neurodegenerative diseases has increased over the last years.This has had a major impact both on patients and their families and has exponentially increased the medical bill by hundreds of billions of Euros.Therefore,understanding the role of environmental and genetic factors in the pathogenesis of PD is crucial to develop preventive strategies.While some authors believe that PD is mainly genetic and that the aging of the society is the principal cause for this increase,different studies suggest that PD may be due to an increased exposure to environmental toxins.In this article we review epidemiological,sociological and experimental studies to determine which hypothesis is more plausible.Our conclusion is that,at least in idiopathic PD(iPD),the exposure to toxic environmental substances could play an important role in its aetiology.