Biology subjects

Lukaszonek, J.

Publications and source records attributed to Lukaszonek, J..

3 recordsLinked to original sources

bioRxiv2024

Trained innate immunity attenuates macrophage efferocytosis of cancer cells

Macrophage phagocytosis has been implicated in regulating anti-tumour immunity. Trained innate immunity (TII), induced via modulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Despite the advances in the study of TII-mediated anti-tumour activity, the impact of TII on the orchestration of phagocytosis in the tumour setting requires further elucidation. Here, we investigated whether macrophage phagocytosis of tumour cells can be modulated through induction of TII. To this end, mice were pre-treated with {beta}-glucan, a fungal-derived agonist of TII, and bone marrow was isolated for macrophage differentiation. Macrophages were then co-cultured with tumour cells that were either apoptotic or opsonised with an antibody recognising a tumour antigen, to mimic efferocytosis and antibody-dependent cellular phagocytosis (ADCP), respectively. While TII did not have any impact in the modulation of ADCP, efferocytosis was decreased in trained macrophages. Along the same line, gene expression analysis demonstrated that mRNA levels of molecules promoting efferocytosis were downregulated in trained macrophages. Trained macrophages exerted decreased levels of active caspase-1 and produced decreased levels of interleukin-1{beta} upon efferocytosis of tumour cells. Our findings reveal a hitherto unknown role of TII in the regulation of anti-tumour immunity and may set the stage for designing new cancer immunotherapeutic approaches targeting macrophage efferocytosis.

immunology↗

bioRxiv2024

Hypoxia-Inducible Factor-1 activated by PIM1 assembles a non-canonical transcription complex and resultant regulon that drives progression of JAK2V617F myeloproliferative neoplasms

Hypoxia-inducible factors (HIFs) are master transcriptional regulators, central to cellular survival under limited oxygen (hypoxia) and frequently activated within malignancy. Malignant context affects the role of HIFs within oncogenesis; however, the mechanisms regulating HIF context-specificities are not well characterised. Applying the JAK2V617F (JVF) model of myeloproliferative neoplasms (MPNs), in which HIF-1 is active in normoxia (20% O2), we sought to determine whether the modality of HIF-1 activation directs its function. We identify that HIF-1 is stabilised in JVF cells downstream of STAT1/5 signalling and upregulation of PIM1: PIM1 mediates phosphorylation of HIF-1 (Thr498/Ser500) in JVF cells that inhibits proteasomal degradation. PIM1 inhibition eradicates HIF-1 from JVF cells. Applying a single-input dual-omics output chromatin interactome methodology (DOCIA), we define JVF-specific transcription cofactors and genomic redistribution of HIF-1, and a JVF-HIF-1 regulon in primary haematopoietic stem/progenitor cells. In a cohort of 172 JVF-MPN patients, we observe significant association of the JVF-HIF-1 regulon (but strikingly, not canonical HIF-1 genes) with disease severity, progression, and patient survival. Finally, we identify a core set of JVF-HIF-1 targets significantly associated with spontaneous transformation of MPNs to AML. Our findings identify that HIF-1 activation by the JVF-PIM1 axis substantially alters its function, and that this reprogramming drives MPN disease progression, restoring the potential for targeted therapies that delineate HIF-1 activity co-opted by malignancy from essential roles within physiological oxygen homeostasis. Key PointsO_LIHIF-1 activation via PIM1 in JAK2V617F-MPNs drives non-canonical transcription complex formation/function. C_LIO_LIThe JAK2V617F-HIF-1 regulon drives MPN disease progression, transformation to AML and worse patient outcomes. C_LI

cancer biology↗

bioRxiv2024

Macrophage-derived developmental endothelial locus 1 (DEL-1) expression promotes an immunoprotective phenotype in experimental visceral leishmaniasis.

The identification of tissue-derived homeostatic molecules regulating immune plasticity is essential for understanding the role of macrophages in immune responses to intra-phagosomal pathogens. Developmental endothelial locus-1 (DEL-1) is a functionally versatile homeostatic factor capable of inhibiting the onset of inflammation and promoting inflammation resolution, but its role in the response to intracellular infections has not been previously addressed. Leishmania, causative agents of the neglected tropical disease leishmaniasis, are intra-phagosomal parasites that establish a replicative niche within macrophages. Here, using a well-established murine model of visceral infection with Leishmania donovani, we establish DEL-1 as a novel regulator of immunity to this infection. Parasite burden was significantly higher in B6.Edil3-/- (Del1-KO) compared to wild type B6 mice, as determined by whole body IVIS imaging, largely as a result of increased liver parasite load. However, lack of DEL-1 enhanced hepatomegaly and enhanced granulomatous inflammation. Conversely, parasite burden and the formation of large granulomas was reduced in mice overexpressing DEL-1 in macrophages but not in endothelial cells. Our findings reveal a hitherto unknown role of DEL-1 in the immune response to L. donovani infection and may represent a novel approach to mitigate immunopathology.

immunology↗