Biology subjects

Azam, T.

Publications and source records attributed to Azam, T..

3 recordsLinked to original sources

bioRxiv2026

OLT1177 (Dapansutrile) inhibits Gasdermin D-dependent IL-1β Release and Pyroptotic Cell Death in Bone Marrow-derived Macrophages

Gasdermins are a family of pore-forming proteins that regulate the release of pro-inflammatory cytokine, interleukin-1{beta} (IL-1{beta}) from infected or PAMP-stimulated cells. During infection or injury, IL-1{beta} is released by both human and mouse macrophages. IL-1{beta} release from mouse macrophages is associated with cell death, often termed "pyroptosis". Mouse macrophages undergoing pyroptosis assemble an exit channel termed gasdermin D (GSDMD). Both the processing of IL-1{beta} and the formation of the exit channel are caspase-1 dependent. Here, in bacterial endotoxin, lipopolysaccharide (LPS), treated mouse bone marrow-derived macrophages (BMDMs), we studied the pharmacologic inhibition of the intracellular nucleotide-binding domain, leucine-rich-containing family, pyrin domain- containing-3 (NLRP3) inflammasome by OLT1177. BMDMs stimulated with LPS plus the potassium efflux inducer nigericin triggered the formation of the NLRP3 inflammasome. Treatment of these BMDMs with OLT1177 suppressed cell death by 42% and ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain)-speck formation by approximately 60%. In addition, OLT1177 dose-dependently inhibited IL-1{beta}, CCL3, and myeloperoxidase (MPO) secretion and the pore-forming (GSDMD) from LPS-primed BMDMs, suggesting the existence of a vicious cycle controlled by IL-1{beta} release. Overall, our study demonstrates that OLT1177 prevents IL-1{beta} release from BMDMs by inhibiting caspase-1 and the conversion of (GSDMD) into its active N-terminal fragment (GSDMD-N). This study thus supports the concept that orally administered OLT1177 can be used to prevent local as well as systemic inflammation in humans.

immunology↗

bioRxiv2026

Hormonal control of postmitotic neuronal identity

Developmental transcriptional programs establish neuronal diversity and circuit assembly, but how these regulators continue to shape and preserve neuronal identity remains unresolved. The Drosophila central complex comprises precisely wired circuits of diverse neuronal types that coordinate complex behaviors. Within this structure, dorsal fan-shaped body (dFB) neurons integrate internal-state signals to regulate sleep, feeding, and energy homeostasis, yet how distinct dFB subtypes are specified and maintained remains unknown. More broadly, whether developmental transcription factors continue to act in mature neurons to preserve neuronal identity is poorly understood. Here, we define the developmental origin and molecular regulation of neuronal identity in 84C10-labelled dFB neurons that innervate layers 6-7 of the FB and contribute to nutrient sensing and metabolic adaptation. Using lineage tracing, clonal analysis, and birth dating, we show that dFB neurons are generated late in development and arise from two distinct type II neural stem cell lineages, dorsolateral 1 and dorsomedial 4. These dFB neurons continue to express the late temporal transcription factor, ecdysone-induced protein 93 (E93), in adulthood. Post-mitotic depletion of E93 results in progressive neuronal loss and ectopic expansion of axonal arborizations across FB layers and, notably, a marked reduction in vesicular glutamate transporter (vGLUT) expression. These defects are accompanied by impaired increases in fat-to-lean mass ratios in response to high-sugar feeding. Together, our findings identify E93 as a post-mitotically retained temporal transcription factor that maintains neuronal survival, laminar connectivity, and neurotransmitter identity, revealing that developmental temporal programs are redeployed in adulthood to sustain neuronal identity and function.

neuroscience↗

bioRxiv2023

IL-38 regulates intestinal stem cell homeostasis by inducing WNT signaling and beneficial IL-1beta secretion

The IL-1 Family member IL-38 has been characterized primarily as an anti-inflammatory cytokine in human and mouse models of systemic diseases. Here, we examined the role of IL-38 in the murine small intestine (SI). Immunostaining of SI revealed that IL-38 expression partially confines to intestinal stem cells. Cultures of intestinal organoids reveal IL-38 functions as a growth factor by increasing organoid size via inducing WNT3a. In contrast, organoids from IL-38 deficient mice develop more slowly. This reduction in size is likely due to downregulation of intestinal stemness markers (i.e., Fzd5, Ephb2, Olfm4) expression compared with wild type organoids. IL-38 binding to IL-1R6 is postulated to recruit the co-receptor IL-1R9. Therefore, to analyze the molecular mechanisms of IL-38 signaling, we also examined organoids from IL-1R9 deficient mice. Unexpectedly, these organoids, although significantly smaller than wild type, respond to IL-38, suggesting that IL-1R9 is not involved in IL-38 signaling in the stem cell crypt. Nevertheless, silencing of IL-1R6 disabled the organoid response to the growth property of IL-38, thus suggesting IL-1R6 as the main receptor used by IL-38 in the crypt compartment. In organoids from wild type mice, IL-38 stimulation induced low concentrations of IL-1{beta} which contribute to organoid growth. However, high concentrations of IL-1{beta} have detrimental effects on the cultures that were prevented by treatment with recombinant IL-38. Overall, our data demonstrate an important regulatory function of IL-38 as a growth factor, and as an anti-inflammatory molecule in the SI, maintaining homeostasis. SignificanceThe IL-1 family member IL-38 has been characterized primarily as an anti-inflammatory cytokine for systemic diseases. Here we describe a fundamental role of IL-38 in driving intestinal stem cell differentiation through the upregulation of WNT3a and IL-1{beta}. Our findings reveal a dual role of IL-38 in regulating intestinal functions; (a) in resting conditions IL-38 maintains intestinal homeostasis, driving WNT3a production and organoid budding, whereas (b) in highly inflamed conditions, IL-38 contributes to proper recovery, by exerting anti-inflammatory activities. Thus, we demonstrate a pivotal role of IL-38 in driving tissue turnover and maintenance of homeostasis in intestinal health.

cell biology↗