Biology subjects

Collino, M.

Publications and source records attributed to Collino, M..

4 recordsLinked to original sources

bioRxiv2023

OxPhos in adipose tissue macrophages regulated by BTK enhances their M2-like phenotype and confers a systemic immunometabolic benefit in obesity

Brutons tyrosine kinase (BTK) is a non-receptor bound kinase involved in pro-inflammatory signalling in activated macrophages, however, its role within adipose tissue macrophages remains unclear. We have demonstrated that BTK signalling regulates macrophage M2-like polarisation state by up-regulating subunits of mitochondrially encoded electron transport chain Complex I (ND4 and NDL4) and Complex IV (mt-CO1, mt-CO2 and mt-CO3) resulting in an enhanced rate of oxidative phosphorylation (OxPhos) in an NF-{kappa}B independent manner. Critically, BTK expression is elevated in adipose tissue macrophages from obese individuals with diabetes, while key mitochondrial genes (mtC01, mtC02 and mtC03) are decreased in inflammatory myeloid cells from obese individuals. Inhibition of BTK signalling either globally (Xid mice) or in myeloid cells (LysMCreBTK), or therapeutically (Acalabrutinib) protects HFD-fed mice from developing glycaemic dysregulation by improving signalling through the IRS1/Akt/GSK3b pathway. The beneficial effects of acalabrutinib treatment are lost in macrophage ablated mice. Inhibition of BTK signalling in myeloid cells but not B-cells, induced a phenotypic switch in adipose tissue macrophages from a pro-inflammatory M1-state to a pro-resolution M2-like phenotype, by shifting macrophage metabolism towards OxPhos. This reduces both local and systemic inflammation and protects mice from the immunometabolic consequences of obesity. Therefore, in BTK we have identified a macrophage specific, druggable target that can regulate adipose tissue polarisation and cellular metabolism that can confer systematic benefit in metabolic syndrome. Article high lightsObesity and diabetes are associated with inflammation, particularly within the adipose tissue. We have found a new druggable target called Brutons tyrosine kinase (BTK) that is highly expressed in adipose tissue macrophages. When BTK is inhibited in macrophages, it allows these cells to undergo a phenotypic switch towards an M2-like pro-resolution macrophage. This achieved by increasing expression of key mitochondrially encoded components of the electron transport chain allowing for enhanced OxPhos. Inhibition of BTK signalling in myeloid cells but not B-cells protects HFD-fed mice from developing glycaemic dysregulation.

pathology↗

bioRxiv2022

Inhibition of the JAK/STAT pathway with baricitinib reduces the multiple organ dysfunction caused by hemorrhagic shock in rats

ObjectiveThe aim of this study was to investigate (a) the effects of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway inhibitor (baricitinib) on the multiple organ dysfunction syndrome (MODS) in a rat model of hemorrhagic shock (HS) and (b) whether treatment with baricitinib attenuates the activation of JAK/STAT, NF-{kappa}B and NLRP3 caused by HS. BackgroundPost-traumatic MODS, which is in part due to excessive systemic inflammation, is associated with high morbidity and mortality. The JAK/STAT pathway is a regulator of numerous growth factor and cytokine receptors and, hence, is considered a potential master regulator of many inflammatory signaling processes. However, its role in trauma-hemorrhage is unknown. MethodsAn acute HS rat model was performed to determine the effect of baricitinib on MODS. The activation of JAK/STAT, NF-{kappa}B and NLRP3 pathways were analyzed by western blotting in the kidney and liver. ResultsWe demonstrate here for the first time that treatment with baricitinib (during resuscitation following severe hemorrhage) attenuates the organ injury and dysfunction and the activation of JAK/STAT, NF-{kappa}B and NLRP3 pathways caused by HS in the rat. ConclusionsOur results point to a role of the JAK/STAT pathway in the pathophysiology of the organ injury and dysfunction caused by trauma/hemorrhage and indicate that JAK inhibitors, such as baricitinib, may be repurposed for the treatment of the MODS after trauma and/or hemorrhage.

pharmacology and toxicology↗

bioRxiv2021

Inhibition of Bruton's tyrosine kinase activity attenuates trauma-induced multiple organ dysfunction in rats

ObjectiveThe aim of this study was to investigate (a) the potential of the Brutons tyrosine kinase (BTK) inhibitors (BTKi) acalabrutinib and fenebrutinib to reduce multiple organ dysfunction syndrome (MODS) in acute and chronic hemorrhagic shock (HS) rat models and (b) whether treatment with either acalabrutinib or fenebrutinib attenuates BTK, NF-{kappa}B and NLRP3 activation in HS. BackgroundThe MODS caused by an excessive systemic inflammatory response following trauma is associated with a high morbidity and mortality. The protein BTK is known to play a role in the activation of the NLRP3 inflammasome, which is a key component of the innate inflammatory response. However, its role in trauma-hemorrhage is unknown. MethodsAcute and chronic HS rat models were performed to determine the influence of acalabrutinib or fenebrutinib on MODS. The activation of BTK, NF-{kappa}B and NLRP3 pathways were analyzed by western blot in the kidney. ResultsWe demonstrated that (a) HS caused organ injury and/or dysfunction and hypotension (post resuscitation) in rats, while (b) treatment of HS-rats with either acalabrutinib or fenebrutinib attenuated the organ injury and dysfunction in acute and chronic HS models and (c) reduced the activation of BTK, NF-{kappa}B and NLRP3 pathways in the kidney. ConclusionOur results point to a role of BTK in the pathophysiology of organ injury and dysfunction caused by trauma/hemorrhage and indicate that BTK inhibitors may be repurposed as a potential therapeutic approach for MODS after trauma and/or hemorrhage. MINI-ABSTRACTThis study evaluated the role of Brutons tyrosine kinase (BTK) in trauma/hemorrhage. Patients with trauma had elevated gene expression of BTK. The BTK inhibitors acalabrutinib (irreversible) and fenebrutinib (reversible) attenuated the trauma-induced multiple organ dysfunction in rats with hemorrhagic shock, indicating that BTK could be a potential therapeutic target.

pharmacology and toxicology↗

bioRxiv2019

Inhibition of Bruton’s tyrosine kinase reduces NF-kB and NLRP3 inflammasome activity preventing insulin resistance and microvascular disease

Activation of inflammatory pathways in myeloid cells initiates insulin resistance leading to the development of type-2 diabetes and microvascular disease. Currently, there are no therapies available that target inflammation in T2D or microvascular disease. In the present study we investigate if Brutons tyrosine kinase (BTK) may represent a novel therapeutic target using the FDA approved medication ibrutinib. Ibrutinib treatment protected high fat diet (HFD)-fed mice from developing insulin resistance and improved glycaemic control by restoring signalling through IRS-1/Akt/GSK-3{beta} pathway. These improvements were independent of body weight and calorific intake. Treatment with ibrutinib to mice fed a HFD reduced NF-{kappa}B and reduced inflammatory gene expression, this was coupled with decreased activation of the NLRP3 inflammasome in the diabetic liver and kidney. Ibrutinib treatment also protected mice from the development of diabetic nephropathy by reducing monocyte/macrophage infiltration due to reduced expression of the pro-inflammatory chemokines. Ibrutinib treatment to human monocyte derived macrophages significantly reduced pro-inflammatory gene expression and a significant reduction in IL-1{beta} and TNF after LPS stimulation. In the present study we provide proof of concept evidence that BTK is a novel therapeutic target for the treatment of T2D and ibrutinib may be a candidate for drug repurposing in T2D.

systems biology↗