An overview of host immune responses against Leishmania spp. infections.

Leishmania spp. infections pose a significant global health challenge, affecting approximately 1 billion people across more than 88 endemic countries. This unicellular, obligate intracellular parasite causes a spectrum of diseases, ranging from localized cutaneous lesions to systemic visceral infections.

Imbalanced VWF-ADAMTS13 axis contributes to the detrimental impact of a preceding respiratory tract infection on stroke.

Respiratory tract infections (RTIs) caused by bacteria or viruses are associated with stroke severity. Recent studies have revealed an imbalance in the von Willebrand factor (VWF)-ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) axis in patients with RTIs, including coronavirus disease 2019. We examined whether this imbalance contributes to RTI-mediated stroke severity.

A comprehensive review of sensors of radiation-induced damage, radiation-induced proximal events, and cell death.

Radiation, a universal component of Earth's environment, is categorized into non-ionizing and ionizing forms. While non-ionizing radiation is relatively harmless, ionizing radiation possesses sufficient energy to ionize atoms and disrupt DNA, leading to cell damage, mutation, cancer, and cell death. The extensive use of radionuclides and ionizing radiation in nuclear technology and medical applications has sparked global concern for their capacity to cause acute and chronic illnesses.

Investigating the role of Caspase-1 in a mouse model of Juvenile X-linked Retinoschisis.

Purpose: Previous studies have reported Caspase-1 () is upregulated in mouse models of Juvenile X-linked Retinoschisis (XLRS), however no functional role for in disease progression has been identified. We performed electroretinogram (ERG) and standardized optical coherence tomography (OCT) in mice deficient in the Retinoschisin-1 () and and Caspase-11 genes (-KO ) to test the hypothesis that may play a role in disease evolution and or severity of disease. Currently, no studies have ventured to investigate the longer-term effects of on phenotypic severity and disease progression over time in XLRS, and specifically the effect on electroretinogram.

LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2-GSDMD Axis-Mediated Gut Inflammation.

Leucine-rich repeat kinase 2 (LRRK2) is a serine-threonine protein kinase belonging to the ROCO protein family. Within the kinase domain of LRRK2, a point mutation known as LRRK2 G2019S has emerged as the most prevalent variant associated with Parkinson's disease. Recent clinical studies have indicated that G2019S carriers have an elevated risk of cancers, including colon cancer.

LRRK2 G2019S promotes the development of colon cancer via modulating intestinal inflammation.

LRRK2 G2019S is the most prevalent variant associated with Parkinson's disease (PD), found in 1-3% of sporadic and 4-8% of familial PD cases. Intriguingly, emerging clinical studies have suggested that LRRK2 G2019S carriers have an increased risk of cancers including colorectal cancer. However, the underlying mechanisms of the positive correlation between LRRK2-G2019S and colorectal cancer remain unknown.

Chalcone: A potential scaffold for NLRP3 inflammasome inhibitors.

Overactivated NLRP3 inflammasome has been shown to associate with an increasing number of disease conditions. Activation of the NLRP3 inflammasome results in caspase-1-catalyzed formation of active pro-inflammatory cytokines (IL-1β and IL-18) resulting in pyroptosis. The multi-protein composition of the NLRP3 inflammasome and its sensitivity to several damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) make this extensively studied inflammasome an attractive target to treat chronic conditions.

CD47 halts -deficient neutrophils from provoking lethal inflammation.

Mice with SHP1 proteins, which have a single amino acid substitution from tyrosine-208 residue to asparagine (hereafter mice), develop an autoinflammatory disease with inflamed footpads. Genetic crosses to study CD47 function in mice bred × mice that were not born at the expected Mendelian ratio. bone marrow cells, when transferred into lethally irradiated -deficient mice, caused marked weight loss and subsequent death.

AIM2 sensors mediate immunity to infection in hepatocytes.

Malaria, caused by parasites is a severe disease affecting millions of people around the world. undergoes obligatory development and replication in the hepatocytes, before initiating the life-threatening blood-stage of malaria. Although the natural immune responses impeding infection and development in the liver are key to controlling clinical malaria and transmission, those remain relatively unknown.

CD4 expression in effector T cells depends on DNA demethylation over a developmentally established stimulus-responsive element.

The epigenetic patterns that are established during early thymic development might determine mature T cell physiology and function, but the molecular basis and topography of the genetic elements involved are not fully known. Here we show, using the Cd4 locus as a paradigm for early developmental programming, that DNA demethylation during thymic development licenses a novel stimulus-responsive element that is critical for the maintenance of Cd4 gene expression in effector T cells. We document the importance of maintaining high CD4 expression during parasitic infection and show that by driving transcription, this stimulus-responsive element allows for the maintenance of histone H3K4me3 levels during T cell replication, which is critical for preventing de novo DNA methylation at the Cd4 promoter.

Hemozoin-mediated inflammasome activation limits long-lived anti-malarial immunity.

During acute malaria, most individuals mount robust inflammatory responses that limit parasite burden. However, long-lived sterilizing anti-malarial memory responses are not efficiently induced, even following repeated Plasmodium exposures. Using multiple Plasmodium species, genetically modified parasites, and combinations of host genetic and pharmacologic approaches, we find that the deposition of the malarial pigment hemozoin directly limits the abundance and capacity of conventional type 1 dendritic cells to prime helper T cell responses.

Chalcone and its analogs: Therapeutic and diagnostic applications in Alzheimer's disease.

Chalcone [(E)-1,3-diphenyl-2-propene-1-one], a small molecule with α, β unsaturated carbonyl group is a precursor or component of many natural flavonoids and isoflavonoids. It is one of the privileged structures in medicinal chemistry. It possesses a wide range of biological activities encouraging many medicinal chemists to study this scaffold for its usefulness to oncology, infectious diseases, virology and neurodegenerative diseases including Alzheimer's disease (AD).

Reconciling protective and pathogenic roles of the NLRP3 inflammasome in leishmaniasis.

Leishmaniasis is a global health problem that affects more than 2 billion people worldwide. Recent advances in research have demonstrated critical roles for cytoplasmic sensors and inflammasomes during Leishmania spp. infection and pathogenesis.

Neutro"feels" lethal toxin.

Discussion on lethal toxin-induced acute IL-1β production as dependent on NLRP1b and caspase-1, PAD4, cell-free DNA and neutrophils.

Ets-2 deletion in myeloid cells attenuates IL-1α-mediated inflammatory disease caused by a Ptpn6 point mutation.

The SHP-1 protein encoded by the Ptpn6 gene has been extensively studied in hematopoietic cells in the context of inflammation. A point mutation in this gene (Ptpn6) causes spontaneous inflammation in mice, which has a striking similarity to neutrophilic dermatoses in humans. Recent findings highlighted the role of signaling adapters and kinases in promoting inflammation in Ptpn6 mice; however, the underlying transcriptional regulation is poorly understood.

Recent Advances in Lipopolysaccharide Recognition Systems.

Lipopolysaccharide (LPS), commonly known as endotoxin, is ubiquitous and the most-studied pathogen-associated molecular pattern. A component of Gram-negative bacteria, extracellular LPS is sensed by our immune system via the toll-like receptor (TLR)-4. Given that TLR4 is membrane bound, it recognizes LPS in the extracellular milieu or within endosomes.

Innate immune priming in the absence of TAK1 drives RIPK1 kinase activity-independent pyroptosis, apoptosis, necroptosis, and inflammatory disease.

RIPK1 kinase activity has been shown to be essential to driving pyroptosis, apoptosis, and necroptosis. However, here we show a kinase activity-independent role for RIPK1 in these processes using a model of TLR priming in a TAK1-deficient setting to mimic pathogen-induced priming and inhibition. TLR priming of TAK1-deficient macrophages triggered inflammasome activation, including the activation of caspase-8 and gasdermin D, and the recruitment of NLRP3 and ASC into a novel RIPK1 kinase activity-independent cell death complex to drive pyroptosis and apoptosis.

The nonreceptor tyrosine kinase SYK drives caspase-8/NLRP3 inflammasome-mediated autoinflammatory osteomyelitis.

Chronic recurrent multifocal osteomyelitis (CRMO) in humans can be modeled in mice, which carry a missense mutation in the proline-serine-threonine phosphatase-interacting protein 2 () gene. As disease in mice, the experimental model analogous to human CRMO, is mediated specifically by IL-1β and not by IL-1α, delineating the molecular pathways contributing to pathogenic IL-1β production is crucial to developing targeted therapies. In particular, our earlier findings support redundant roles of NLR family pyrin domain-containing 3 (NLRP3) and caspase-1 with caspase-8 in instigating However, the signaling components upstream of caspase-8 and pro-IL-1β cleavage in mice are not well-understood.

Leishmania major degrades murine CXCL1 - An immune evasion strategy.

Leishmaniasis is a global health problem with an estimated report of 2 million new cases every year and more than 1 billion people at risk of contracting this disease in endemic areas. The innate immune system plays a central role in controlling L. major infection by initiating a signaling cascade that results in production of pro-inflammatory cytokines and recruitment of both innate and adaptive immune cells.

Loss of RHBDF2 results in an early-onset spontaneous murine colitis.

Inflammatory bowel disease (IBD) is a heterogeneous group of inflammation-mediated pathologies that include Crohn's disease and ulcerative colitis and primarily affects the colon and small intestine. Previous studies have shown that a disintegrin and metalloprotease (ADAM) 17, a membrane-bound sheddase, capable of cleaving the proinflammatory cytokine TNF and epidermal growth factor receptor ligands, plays a critical role in maintaining gut homeostasis and modulating intestinal inflammation during IBD. Rhomboid 5 homolog 2 (RHBDF2), a catalytically inactive member of the rhomboid family of intramembrane serine proteases, was recently identified as a crucial regulator of ADAM17.

Cutting Edge: Dysregulated CARD9 Signaling in Neutrophils Drives Inflammation in a Mouse Model of Neutrophilic Dermatoses.

Mice homozygous for the Y208N amino acid substitution in the carboxy terminus of SHP-1 (referred to as mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in mice is characterized by persistent footpad swelling and suppurative inflammation. Recently, in addition to IL-1α and IL-1R signaling, we demonstrated a pivotal role for RIPK1, TAK1, and ASK1 in promoting inflammatory disease in mice.

Innate immune adaptor MyD88 deficiency prevents skin inflammation in SHARPIN-deficient mice.

Mice deficient in SHANK-associated RH domain-interacting protein (SHARPIN), a component of the linear ubiquitin chain assembly complex (LUBAC), develop a spontaneous inflammatory disorder with pathologic hallmarks similar to atopic dermatitis and psoriasis in humans. Previous studies identified the crucial role of components of the TNF and IL-1 signaling pathways in the progression of disease in SHARPIN-deficient mice. However, an innate immune adaptor or sensor that relates to the disease progression has remained unknown.