Biology subjects

Atif, S. M.

Publications and source records attributed to Atif, S. M..

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↗

bioRxiv2024

Epithelial heme oxygenase-1 enhances colonic tumorigenesis by inhibiting ferroptosis

Induction of heme oxygenase-1 (HO-1/Hmox1) is broadly considered cytoprotective, but the role of colonic epithelial HO-1 in colitis-associated tumorigenesis is poorly defined. HO-1 catabolizes heme, releasing ferrous iron, a key driver of oxidative stress and lipid peroxidation. We observed that colonic epithelial HO-1 is induced during colitis and tumorigenesis. We also found that HO-1 is upregulated in ferroptosis-inducing conditions in murine and human colonic epithelial organoids, and correlated with lipid peroxidation and ferroptosis markers in colonic tumors. In colonic epithelial organoids exposed to heme, deletion of Hmox1 amplified a compensatory oxidative stress and detoxification transcriptional program, likely reflecting unresolved oxidative and non-oxidative toxicity from heme. In vivo, epithelial HO-1 deficient mice developed significantly fewer and smaller tumors compared to littermate controls in a colitis-associated tumorigenesis model, despite similar inflammatory injury. Tumors from knockout mice exhibited reduced iron levels, decreased lipid peroxidation, lower oxidative DNA damage, and decreased proliferation. Single-cell RNA sequencing of tumor epithelial cells revealed a shift from a proliferative to a stress-adaptive program with loss of HO-1. These findings identify epithelial HO-1 as a context-dependent regulator of tumorigenesis: protective against acute heme toxicity, but promoting iron-dependent oxidative damage and proliferation in the setting of chronic inflammation.

cancer biology↗

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↗