RESUMEN
The NOD1/2-RIPK2 is a key cytosolic signaling complex that activates NF-κB pro-inflammatory response against invading pathogens. However, uncontrolled NF-κB signaling can cause tissue damage leading to chronic diseases. The mechanisms by which the NODs-RIPK2-NF-κB innate immune axis is activated and resolved remain poorly understood. Here, we demonstrate that bacterial infection induces the formation of endogenous RIPK2 oligomers (RIPosomes) that are self-assembling entities that coat the bacteria to induce NF-κB response. Next, we show that autophagy proteins IRGM and p62/SQSTM1 physically interact with NOD1/2, RIPK2 and RIPosomes to promote their selective autophagy and limit NF-κB activation. IRGM suppresses RIPK2-dependent pro-inflammatory programs induced by Shigella and Salmonella. Consistently, the therapeutic inhibition of RIPK2 ameliorates Shigella infection- and DSS-induced gut inflammation in Irgm1 KO mice. This study identifies a unique mechanism where the innate immune proteins and autophagy machinery are recruited together to the bacteria for defense as well as for maintaining immune homeostasis.
Asunto(s)
Infecciones Bacterianas , FN-kappa B , Ratones , Animales , FN-kappa B/metabolismo , Ratones Endogámicos NOD , Autofagia , Inmunidad Innata , HomeostasisRESUMEN
Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid-sensing pathways leading to interferon-stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their p62-dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS-STING and RIG-I-MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes , Autoinmunidad , Animales , Enfermedades Autoinmunes/genética , Autoinmunidad/genética , Autofagia , Ratones , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Transducción de SeñalRESUMEN
Di-2-ethylhexyl phthalate (DEHP) is the most commonly preferred synthetic organic chemical in plastics and its products for making them ductile, flexible and durable. As DEHP is not chemically bound to the macromolecular polymer of plastics, it can be easily leached out to accumulate in food and environment. Our recent report advocated that exposure to DEHP significantly transformed the innate bottom-dwelling and scototaxis behaviour of zebrafish. Our present study aimed to understand the possible role of DEHP exposure pertaining towards the development of aggressive behaviour and its association with amplified monoamine oxidase activity and neurodegeneration in the zebrafish brain. As heightened monoamine oxidase (MAO) is linked with genesis of aggressive behaviour, our observation also coincides with DEHP-persuaded aggressive neurobehavioral transformation in zebrafish. Our preliminary findings also showed that DEHP epitomized as a prime factor in transforming native explorative behaviour and genesis of aggressive behaviour through oxidative stress induction and changes in the neuromorphology in the periventricular grey zone (PGZ) of the zebrafish brain. With the finding demarcating towards heightened chromatin condensation in the PGZ of zebrafish brain, our further observation by immunohistochemistry showed a profound augmentation in apoptotic cell death marker cleaved caspase 3 (CC3) expression following exposure to DEHP. Our further observation by immunoblotting study also demarcated a temporal augmentation in CC3 and tyrosine hydroxylase expression in the zebrafish brain. Therefore, the gross findings of the present study delineate the idea that chronic exposure to DEHP is associated with MAO-instigated aggressive neurobehavioral transformation and neurodegeneration in the zebrafish brain.
Asunto(s)
Agresión , Conducta Animal , Encéfalo , Dietilhexil Ftalato , Monoaminooxidasa , Pez Cebra , Animales , Dietilhexil Ftalato/toxicidad , Monoaminooxidasa/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Encéfalo/metabolismo , Conducta Animal/efectos de los fármacos , Agresión/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/patologíaRESUMEN
Squamous cell carcinoma (SCC) of the colon is a rare malignancy and usually a pathological surprise. Clinical presentation is usually very similar to adeno carcinoma variety. We report a case of a 56 year old male with primary SCC of caecum presenting as small bowel obstruction and managed with surgery and adjuvant chemotherapy. It was labelled as primary SCC after extensive search for other primary malignant SCC in body with possible metastasis to caecum. Due to rarity of the disease and lack of literature standardized protocols for neo-adjuvant and adjuvant therapy are not available.
RESUMEN
Over expression of drug efflux transporters such as P-glycoprotein (P-gp) cumulatively leading to multidrug resistance (MDR) embodies a major hindrance for successful cancer therapy. A paradigm nanomedicinal approach involving an anticancer drug and modulators of drug resistance within one multifunctional nanocarrier-based delivery system represent an ideal modality for the treatment of MDR. In this regards, we have developed a cationic polymeric nanoparticulate system loaded with MDR1-siRNA and doxorubicin. Results indicated augmented synergistic effect of combinational nanoformulation in overcoming MDR in MCF-7/ADR cells. Therefore, the above regime could be a promising co-delivery system for effective therapy of drug resistant breast cancer.