Biology subjects

Kuriakose, G.

Publications and source records attributed to Kuriakose, G..

4 recordsLinked to original sources

bioRxiv2026

Transient efferocytosis-induced activation of IKKβ reprograms macrophages to promote tissue resolution

The clearance of apoptotic cells by macrophages, termed efferocytosis, reprograms macrophages to a resolution/repair phenotype, and pathologic defects in efferocytosis drive many chronic inflammatory diseases. Previous studies have elucidated numerous downstream pro-resolving pathways activated by efferocytosis, but whether there exists a common upstream trigger of these pathways remains unknown. Here, we report that efferocytosing macrophages surprisingly use a signaling module typically associated with inflammation to carry out this key initiating role in tissue resolution. The binding of apoptotic cells to the MerTK receptor triggers a rapid and transient activation of inhibitor of nuclear factor (NF) kappa-B kinase subunit beta (IKK{beta}), leading to NF{kappa}B and p38-signal transducer and activator of transcription 3 (STAT3) signaling and then activation of several key downstream pro-resolving pathways, including interleukin-10 (IL-10) production, continuing efferocytosis, and regulatory T (Treg) cell expansion. The upstream IKK{beta} pathway and the downstream resolution pathways are linked through several intermediary molecules, including the transcription factor Myc, the epigenetic modifier ten-eleven translocation-2 (TET2), and the immune checkpoint protein programmed cell death ligand 1 (PD-L1). Deletion of macrophage IKK{beta} in vivo blocks the above resolution pathways and compromises tissue repair in two efferocytosis-mediated repair settings: resolution of thymic injury after dexamethasone-induced thymocyte apoptosis; and, most importantly, atherosclerosis regression induced by low-density lipoprotein (LDL)-lowering, which is highly relevant to the prevention of cardiovascular disease in humans. These findings illustrate the existence of a unifying upstream signal for efferocytosis-induced resolution, which could suggest new therapeutic strategies to enhance multiple tissue resolution pathways and to optimize anti-inflammatory therapies by avoiding blocking IKK{beta}-NF{kappa}B/p38-mediated resolution.

immunology↗

bioRxiv2025

Prelamin A Does Not Promote Atherosclerosis or Vascular Smooth Muscle Loss

BACKGROUNDHutchinson-Gilford progeria syndrome (HGPS) is an accelerated aging disorder characterized by numerous symptoms, including early-onset atherosclerosis, with most patients suffering fatal myocardial infarctions or strokes by the second decade of life. HGPS is caused by mutations in LMNA that lead to expression of an internally truncated, farnesylated prelamin A variant called progerin, which induces loss of vascular smooth muscle cells (VSMCs). Some studies have also reported that accumulation of full-length farnesylated prelamin A, which is normally completely processed to mature non-farnesylated lamin A, can also drive vascular pathology during physiological aging. METHODSTo assess the effects of prelamin A expression on atherosclerosis and aortic VSMCs, we used LmnaL648R/L648R mice that express a prelamin A variant with a lysine to arginine point mutation that prevents its processing to mature lamin A. To determine if prelamin A expression has an impact on atherosclerotic plaques, we crossed LmnaL648R/L648R mice to LDL receptor-deficient Ldlr-/- mice that develop hyperlipidemia on a high-fat diet. RESULTSAtherosclerotic plaque lesion area and necrotic core area were not different in hyperlipidemic LmnaL648R/L648R mice that expressed only prelamin A, and no mature lamin A, compared to hyperlipidemic Lmna+/+ mice that expressed only fully-processed mature lamin A and no prelamin A. Additionally, exclusive prelamin A expression did not result in loss of aortic VSMCs or adventitial thickening in hyperlipidemic LmnaL648R/L648R mice with atherosclerosis at 28 weeks of age. Indeed, aortic vascular smooth muscle remained normal in older LmnaL648R/L648R mice at 52 weeks of age. CONCLUSIONSIn contrast to the prelamin A variant progerin expressed in HGPS, prelamin A does not appear to cause vascular smooth muscle loss, promote atherosclerosis or drive vascular aging.

molecular biology↗

bioRxiv2022

Beyond the metropolis: Street tree densities and resident perceptions on ecosystem services in small urban centers in India

The role of urban street trees has been extensively studied in large metropolises, where they contribute significantly to faunal habitat, provide critical ecosystem services to residents and contribute to human well-being. On the other hand, rapidly urbanizing cities in India have been poorly studied, despite multiple types of irreplaceable losses related to tree cover. However, being early in their urbanization history, these centers also represent opportunity for urban sustainability with potentially high remnant vegetation and human-nature connections. While megacities in developed countries move towards biophilic urban planning and participatory decision making, basic information on tree communities and their perceived services is a bottleneck in achieving these goals in such small urban centers. We assessed the street tree community and resident perceptions of ecosystem service values in Kochi and Panjim, two coastal cities in India under rapid development, through a combination of field measurements (258 transects, 931 trees) and semi-structured interviews (497 individuals). We found that mean street tree density is low in both cities, especially so in Kochi, and corresponds to perceptions of recent change in tree cover (-28% in Kochi, -11% in Panjim). The street tree community in both cities were dominated by ornamental avenue trees such as Albizia saman and Peltophorum pterocarpum, but native coastal species like Cocos nucifera, Terminalia catappa and Thespesia populnea were also common. Despite recent urban growth, residents in both cities reported low value of trees for food, fodder and medicine, but high value for regulating services like shade and water. Moreover, we found strong evidence for aesthetic and cultural values of trees in both cities, including through qualitative interviews. Our study establishes critical baselines for biophilic planning in these small urban centers towards urban sustainability.

ecology↗

bioRxiv2021

Allosteric MAPKAPK2 Inhibitors Improve Plaque Stability in Advanced Atherosclerosis

Atherosclerotic vascular disease resulting from unstable plaques is the leading cause of morbidity and mortality in subjects with type 2 diabetes (T2D), and thus a major therapeutic goal is to discover T2D drugs that can also promote atherosclerotic plaque stability. Genetic or pharmacologic inhibition of mitogen-activated protein kinase-activated protein kinase-2 (MK2) in obese mice improves glucose homeostasis and enhances insulin sensitivity. We developed two novel orally active small-molecule inhibitors of MK2, TBX-1 and TBX-2, and tested their effects on metabolism and atherosclerosis in high-fat Western diet (WD)-fed Ldlr-/- mice. Ldlr-/- mice were first fed the WD to allow atherosclerotic lesions to become established, and the mice were then treated with TBX-1 or TBX-2. Both compounds improved glucose metabolism and lowered plasma cholesterol and triglyceride, without an effect on body weight. Most importantly, the compounds decreased lesion area, lessened plaque necrosis, and increased fibrous cap thickness in the aortic root lesions of the mice. Thus, in a preclinical model of high-fat feeding and established atherosclerosis, MK2 inhibitors improved metabolism and also enhanced atherosclerotic plaque stability, suggesting potential for further clinical development to address the epidemic of T2D associated with atherosclerotic vascular disease.

molecular biology↗