Biology subjects

Diallo, K.

Publications and source records attributed to Diallo, K..

4 recordsLinked to original sources

bioRxiv2025

Macrophages amplify the spontaneous activity of damaged sensory neurons in a human co-culture model of neuropathic pain

Neuropathic pain is a highly prevalent condition for which treatments are hampered by low efficacy and dose-limiting side-effects. Injury to the somatosensory nervous system causes maladaptive plasticity that initiates and maintains chronic pain. Emerging evidence suggests that inflammatory cells of the innate immune system shape the response of the injured nervous system and thereby contribute to the pathogenesis of pain. Data from preclinical models and human patient biopsies have specifically implicated peripheral macrophage populations for a pro-algesic role, yet how these cell types influence damaged sensory neurons and whether they directly contribute to neuronal hyperexcitability is unclear. Here, we have developed an iPSC co-culture system to study the interactions of macrophages and sensory neurons in a fully humanised experimental model. We found that analogous to endogenous counterparts, iPSC-derived macrophages (iMacs) display a dynamic molecular and functional profile that is highly dependent on neuronal state. Co-culture with injured iPSC-derived sensory neurons (iSNs) induces morphological, gene expression, and secretory profile changes in iMacs that are consistent with the response of macrophages to nerve injury in vivo. iMacs in turn amplify spontaneous firing in damaged sensory neurons, implicating macrophages in this cardinal feature of neuropathic pain. These results illustrate the utility of an iPSC-based model to study signalling between these two cell types; they support a role for macrophages in directly amplifying damaged sensory neuron activity and highlight disrupting pathological signalling between these cell types as a promising strategy for future analgesic drug development.

neuroscience↗

bioRxiv2024

PROS1 released by human lung basal cells upon SARS-CoV-2 infection facilitates epithelial cell repair and limits inflammation.

Factors governing the coagulopathy and pneumonitis associated with severe viral infections remain unresolved. We previously found that the expression of protein S (PROS1) is increased in lung epithelium of patients with mild COVID-19 as compared to severe COVID-19. We hypothesised that PROS1 may exert a local effect that protects the upper airway against severe inflammation by modulating epithelial and myeloid cell responses. To test this, in vitro air-interface cultures, seeded from primary healthy human lung epithelial cells, were infected with different SARS-CoV-2 clades. This model, validated by single-cell RNAseq analysis, recapitulated the dynamic cell-profile and pathogenic changes of COVID-19. We showed that PROS1 was located in the basal cells of healthy pseudostratified epithelium. During SARS-Cov-2 infection, PROS1 was released by basal cells, which was partially mediated by interferon. Transcriptome analysis showed that SARS-CoV-2 infection induced proinflammatory phenotypes (CXCL10/11high, PTGS2posF3high, S100A8/A9high) of basal and transitional cells. PROS1 strongly downregulated these cells and transformed the proinflammatory CXCL10/11high basal cells into the regenerative S100A2posKRThigh basal cell phenotype. In addition, SARS-CoV-2 infection elevated M-CSF secretion from epithelium, which induced MERTK, a receptor for PROS1, on monocytes added into 3D lung epithelial culture. We demonstrated that SARS-CoV-2 drives monocyte phenotypes expressing coagulation (F13A1) and complement (C1O) genes. PROS1 significantly downregulated these phenotypes and induced higher expression of MHC class II. Overall, this study demonstrated that the epithelium-derived PROS1 during SARS-CoV-2 infection inhibits the proinflammatory epithelial phenotypes, favours basal cell regeneration, and inhibits myeloid inflammation while enhancing antigen presentation. These findings highlight the importance of basal epithelial cells and PROS1 protection from viral infection induced severe lung pathology. O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/612489v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@324deaorg.highwire.dtl.DTLVardef@994f30org.highwire.dtl.DTLVardef@11de2e0org.highwire.dtl.DTLVardef@11a0fe2_HPS_FORMAT_FIGEXP M_FIG 1) SARS-CoV2 infection of the epithelium results in release of IFN. 2) IFN secretion has an autocrine effect on epithelial cells 3) Infection and IFN cause release of PROS1 from the basal cells, as well as M-CSF from the epithelium 4) PROS1 acts on basal cells which express MERTK, a PROS1 receptor 5) PROS1 downregulated the proinflammatory phenotypes expanded by viral infection, while upregulating KRThigh basal cells with repair phenotypes 6) The secreted M-CSF drives MERTK expression on monocytes in cocultures with epithelium. 7) PROS1 induces downregulation of monocyte clusters characteristic of viral infection that express pro-coagulation and complement genes, while upregulating clusters with higher MHC class II. 8) In summary, PROS1 mediates phenotypic switch of SARS-Cov2 induced pathogenic myeloid clusters with complement and coagulation phenotypes into phenotype with efficient antigen presentation, reduces proinflammatory activation of epithelium and induces epithelial barrier repair, resulting in mild COVID-19. C_FIG

cell biology↗

bioRxiv2020

14-3-3ζ regulates lipolysis by influencing adipocyte maturity

One of the primary metabolic functions of a mature adipocyte is to supply energy via lipolysis, or the catabolism of stored lipids. Hormone-sensitive lipase (HSL) is a critical lipolytic enzyme, and its phosphorylation and subsequent activation by PKA generates phospho-binding sites for 14-3-3 proteins, a ubiquitously expressed family of molecular scaffolds. While we previously identified essential roles of the 14-3-3{zeta} isoform in murine adipogenesis, the presence of 14-3-3 protein binding sites on HSL suggests that 14-3-3{zeta} could also influence mature adipocyte processes like lipolysis. Herein, we demonstrate that 14-3-3{zeta} is necessary for lipolysis in male mice and fully differentiated 3T3-L1 adipocytes, as depletion of 14-3-3{zeta} significantly impaired glycerol and FFA release. Unexpectedly, this was not due to impairments in signaling events underlying lipolysis; instead, reducing 14-3-3{zeta} expression was found to significantly impact adipocyte maturity, as observed by reduced abundance of PPAR{gamma}2 protein and expression of mature adipocytes genes and those associated with de novo triglyceride synthesis and lipolysis. The impact of 14-3-3{zeta} depletion on adipocyte maturity was further examined with untargeted lipidomics, which revealed that reductions in 14-3-3{zeta} abundance promoted the acquisition of a lipidomic signature that resembled undifferentiated, pre-adipocytes. Collectively, these findings reveal a novel aspect of 14-3-3{zeta} in adipocytes, as reducing 14-3-3{zeta} was found to have a negative effect on adipocyte maturity and adipocyte-specific processes like lipolysis.

physiology↗

bioRxiv2019

14-3-3ζ over-expression improves tolerance to acute and chronic cold exposure in male mice via thermogenic-dependent and -independent mechanisms

Following prolonged cold exposure, adaptive thermogenic pathways are activated to maintain homeothermy, and elevations in body temperature are generally associated with UCP1-dependent and -independent increases in energy expenditure. One of the earliest, identified functions of the molecular scaffold, 14-3-3{zeta}, was its role in the synthesis of norepinephrine, a key endogenous factor that stimulates thermogenesis. This suggests that 14-3-3{zeta} may have critical roles in cold-induced thermogenesis. Herein, we report that transgenic over-expression of TAP-14-3-3{zeta} in mice significantly improved tolerance to prolonged cold. When compared to wildtype controls, TAP mice displayed significantly elevated body temperatures and paradoxical decreases in energy expenditure. No changes in {beta}-adrenergic sensitivity or oxidative metabolism were observed; instead, 14-3-3{zeta} over-expression significantly decreased thermal conductance via increased peripheral vasoconstriction. These findings suggest 14-3-3{zeta} mediates alternative, non-thermogenic mechanisms to mitigate heat loss for homeothermy. Our results point to an unexpected role of 14-3-3{zeta} in the regulation of body temperature. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=137 HEIGHT=200 SRC="FIGDIR/small/853184v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1f5b454org.highwire.dtl.DTLVardef@1219a7org.highwire.dtl.DTLVardef@523fb3org.highwire.dtl.DTLVardef@1d41780_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗