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Malassezia spp. induce inflammatory cytokines and activate NLRP3 inflammasomes in phagocytes.

ABSTRACT: Malassezia spp. are common eukaryotic yeasts that colonize mammalian skin. Recently, the authors and others have observed that Malassezia globosa and Malassezia restricta can be found in the intestines in the context of certain diseases, including Crohn's disease and pancreatic cancer. In order to better understand the nature of innate inflammatory responses to these yeasts, inflammatory responses induced by M. restricta and M. globosa in mouse bone marrow-derived Mϕs (BMDM) and dendritic cells (BMDC) are evaluated. While Malassezia yeasts induce proinflammatory cytokine production from both Mϕs and dendritic cells, the levels of production from BMDC were more pronounced. Both M. restricta and M. globosa activated inflammatory cytokine production from BMDC in large part through Dectin2 and CARD9 signaling, although additional receptors appear to be involved in phagocytosis and activation of reactive oxygen production in response to the yeasts. Both M. restricta and M. globosa stimulate production of pro-IL-1β as well as activation of the NLRP3 inflammasome. NLRP3 inflammasome activation by Malassezia fungi requires SYK signaling, potassium efflux and actin rearrangement. Together, the data further the understanding of the coordinated involvement of multiple innate immune receptors in recognizing Malassezia globosa and Malassezia restricta and orchestrating phagocyte inflammatory and antimicrobial responses.

SUBMITTER: Wolf AJ

PROVIDER: S-EPMC7902306 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cardiopulmonary bypass (CPB), the mechanical support required during the majority of cardiac surgeries, causes significant systemic inflammation and multi-organ dysfunction that is especially severe in neonatal patients. Currently, the limited understanding of the molecular mechanisms that underlie CPB-associated inflammation presents a significant barrier to the development of therapeutic interventions. To address this knowledge gap, we performed mRNA sequencing of total circulating leukocytes from neonatal patients undergoing CPB. The transcriptional signatures across 7 time points ranging from pre-CPB, during CPB, to 24 hours post-CPB were found to be dominated by myeloid cells, particularly monocytes. INTERLEUKIN-8 (IL8) and TUMOR NECROSIS FACTOR-α (TNFα) were two inflammatory cytokines specifically and robustly upregulated in the leukocytes from both CPB patients and piglets exposed to CPB. To delineate the mechanism how CPB activates cytokine production, we exposed THP-1 cells, a human monocyte cell line, in vitro to CPB-like conditions including artificial surfaces, high shear stress and cooling/rewarming. The in vitro CPB data recapitulated the in vivo CPB condition in that IL8 and TNFα were strongly upregulated. Shear stress was the major driver of cytokine expression as compared to the temperature or plastic exposure. Extracellular calcium influx was found essential for the shear-stress mediated upregulation of cytokines via the MEK/ERK/AP-1 and Calcineurin/NFAT pathways. After being exposed to CPB conditions, a subpopulation of THP-1 cells died by apoptosis and TNFα-mediated necroptosis, the latter form of which potentially contribute to the post-CPB tissue injuries. Together, our study is the first to elucidate the shear-stress modulated molecular mechanisms leading to systemic inflammation in pediatric CPB and the link between inflammation and organ damage. Calcium signaling pathways and TNFα signaling are novel targets for therapeutic development to improve clinical outcomes. To our knowledge, these are also the first data to implicate necroptosis in CPB and show that shear stress can activate necroptosis.

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Malassezia spp. induce inflammatory cytokines and activate NLRP3 inflammasomes in phagocytes.

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