Biology subjects

Bulek, K.

Publications and source records attributed to Bulek, K..

3 recordsLinked to original sources

bioRxiv2023

TRAF4 is crucial for the propagation of ST2+ memory Th2 cells in IL-33-mediated type 2 airway inflammation

Tumor necrosis factor receptor (TNF)-associated factor 4 (TRAF4) is an important regulator of type 2 responses in the airway; however, the underlying cellular and molecular mechanisms remain elusive. Herein, we generated T cell-specific TRAF4-deficient (CD4cre-Traf4fl/fl) mice and investigated the role of TRAF4 in interleukin (IL)-33 receptor (ST2, suppression of tumorigenicity 2)-expressing memory Th2 cells (ST2+ mTh2) in IL-33-mediated type 2 airway inflammation. We found that in vitro polarized TRAF4-deficient (CD4cre-Traf4fl/fl) ST2+ mTh2 cells exhibited decreased IL-33-induced proliferation as compared with TRAF4-sufficient (Traf4fl/fl) cells. Moreover, CD4cre-Traf4fl/fl mice showed less ST2+ mTh2 cell proliferation and eosinophilic infiltration in the lungs than Traf4fl/fl mice in the preclinical models of IL-33-mediated type 2 airway inflammation. Mechanistically, we discovered that TRAF4 was required for the activation of AKT/mTOR and ERK1/2 signaling pathways as well as the expression of transcription factor Myc and nutrient transporters (Slc2a1, Slc7a1, and Slc7a5), signature genes involved in T cell growth and proliferation, in ST2+ mTh2 cells stimulated by IL-33. Taken together, the current study reveals a previously unappreciated role of TRAF4 in ST2+ mTh2 cells in IL-33-mediated type 2 pulmonary inflammation, opening up avenues for the development of new therapeutic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/528093v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@18a8f48org.highwire.dtl.DTLVardef@1c4e29corg.highwire.dtl.DTLVardef@f98f72org.highwire.dtl.DTLVardef@38aacb_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Mincle-GSDMD-mediated release of IL-1β containing small extracellular vesicles contributes to ethanol-induced liver injury

Background & AimsMacrophage inducible C-type lectin (Mincle) is expressed on Kupffer cells and senses ethanol-induced danger signals released from dying hepatocytes and promotes IL-1{beta} production. However, it remains unclear what and how ethanol-induced Mincle ligands activate downstream signaling events to mediate IL-1{beta} release and contribute to alcohol-associated liver disease (ALD). In this study, we investigated the association of circulating {beta}-glucosylceramide ({beta}-GluCer), an endogenous Mincle ligand, with severity of ALD and examined the mechanism by which {beta}-GluCer engages Mincle on Kupffer cells to release IL-1{beta} in the absence of cell death and exacerbates ALD. Approach and ResultsConcentrations of {beta}-GluCer were increased in serum of patients with severe AH and correlated with disease severity. Challenge of Kupffer cells with LPS and {beta}-GluCer induced formation of a Mincle and Gsdmd-dependent secretory complex containing chaperoned full-length GSDMD (Hsp90-CDC37-NEDD4) with polyubiquitinated pro-IL-1{beta} and components of the Casp8-NLRP3 inflammasome loaded as cargo in small extracellular vesicles (sEV). Gao-binge ethanol exposure to wild-type, but not Mincle-/- and Gsdmd-/-, mice increased release of IL-1{beta} containing sEVs from liver explant cultures. Myeloid-specific deletion of Gsdmd similarly decreased the formation of sEVs by liver explant cultures and protected mice from ethanol-induced liver injury. sEVs collected from ethanol-fed wild-type, but not Gsdmd-/-, mice promoted injury of cultured hepatocytes and, when injected into wild-type mice, aggravated Gao-binge ethanol-induced liver injury. Conclusion{beta}-GluCer functions as a DAMP activating Mincle-dependent GSDMD-mediated formation and release of IL-1{beta}-containing sEVs, which in turn exacerbate hepatocyte cell death and contribute to the pathogenesis of ALD.

immunology↗

bioRxiv2019

TLR5 participates in the TLR4 receptor complex and biases towards MyD88-dependent signaling in environmental lung injury

Lung disease causes significant morbidity and mortality, and is exacerbated by environmental injury, e.g. through lipopolysaccharide (LPS) or ozone (O3). Toll-like receptors (TLRs) orchestrate immune responses to injury by recognizing pathogen- or danger-associated molecular patterns. TLR4, the prototypic receptor for LPS, also mediates inflammation after O3, triggered by endogenous hyaluronan. Regulation of TLR4 signaling is incompletely understood. TLR5, the flagellin receptor, is expressed in alveolar macrophages, and regulates immune responses to environmental injury. Using in vivo animal models of TLR4-mediated inflammations (LPS, O3, hyaluronan), we show that TLR5 impacts the in vivo response to LPS, hyaluronan and O3. We demonstrate that immune cells of human carriers of a dominant negative TLR5 allele have decreased inflammatory response to O3 exposure ex vivo and LPS exposure in vitro. Using primary murine macrophages, we find that TLR5 physically associates with TLR4 and biases TLR4 signaling towards the MyD88 pathway. Our results suggest an updated paradigm for TLR4/TLR5 signaling.

immunology↗