Biology subjects

Huerga Encabo, H.

Publications and source records attributed to Huerga Encabo, H..

3 recordsLinked to original sources

bioRxiv2025

DNMT3A-R882 mutations intrinsically drive dysfunctional neutropoiesis from human haematopoietic stem cells

Clonal haematopoiesis (CH) arises from the expansion of hematopoietic stem cells (HSCs) carrying leukaemia-associated somatic mutations. CH is linked to pathological immune dysregulation and a greater risk of age-related inflammatory diseases. Yet, how CH mutations impact HSC differentiation into immune effector cells remains understudied. Here, we report a single-cell resolution functional and multi-omic investigation of HSC clonal and differentiation dynamics in individuals with DNMT3A-R882 CH. DNMT3A-R882 reshapes the clonal architecture of haematopoiesis towards an aged phylogenetic structure. Functionally, DNMT3A-R882 HSCs produce decreased monocytic output but more abundant and mature neutrophil progeny compared to WT HSCs in the same individual. Whereas DNMT3A-R882 myeloid progenitors display attenuated inflammatory transcriptional programmes, DNMT3A- R882 mature neutrophils acquire proinflammatory and immunomodulatory features typical of maladaptive immunity and CH co-morbidities. Our findings, validated in humanised mice, identify aberrant DNMT3A-R882 HSC-driven neutropoiesis as a key link between CH, immune dysregulation and risk of inflammatory disease.

cell biology↗

bioRxiv2025

Granulocyte Derived Resistin Inhibits Monocyte Maturation and Induces Immune Suppression in CMML

Chronic myelomonocytic leukaemia (CMML) is a haematological malignancy characterised by overlapping myeloid dysplasia and proliferation with persisting monocytosis. While monocytes are the cardinal malignant cell type in CMML, as a stem cell neoplasm the disease clone comprises most lineages and differentiation stages, including granulocytes. To investigate the pathogenic contribution of granulocytes in CMML maintenance and progression, we performed phenotypic, transcriptomic and functional characterization of CMML granulocytes. Compared with healthy age-matched controls, CMML granulocytes exhibit defective maturation with reduced granularity and phagocytic capacity. Transcriptome analysis revealed activation of pathways linked to proliferation, Myc activity and inflammation. Notably, RETN, which encodes the inflammatory mediator resistin, was upregulated approximately 100-fold in CMML granulocytes; but not differentially expressed in CMML PBMNCs, sorted monocytes, or stem and progenitor cells compared to their healthy counterparts. Accordingly, resistin protein levels were 10-fold higher in plasma from CMML patients and higher plasma resistin levels correlate with poor overall survival and AML-free survival. Remarkably, exposure of healthy monocytes to exogenous recombinant resistin inhibited monocyte maturation and macrophage differentiation. Transcriptome analysis of resistin treated monocytes revealed that resistin induces gene signatures related to immune suppression and myeloid-derived suppressor cell phenotype. We found SEMA4A to be a downstream target of resistin and overexpressed in CMML monocytes. Consistent with known roles for SEMA4A, CMML patients displayed higher percentage of Tregs and elevated Th2/Th1 ratio compared with healthy controls and percentage of Tregs corresponding with associated resistin levels. Furthermore, we demonstrated that resistin directly skews the Th2/Th1 ratio via binding to monocytes. In conclusion, we showed that immature granulocytes in CMML produce high levels of resistin, which contributes to defective monocyte maturation and immune suppression.

cancer biology↗

bioRxiv2020

Protective role of neuronal and lymphoid cannabinoid CB2 receptors in neuropathic pain

Cannabinoid CB2 receptor (CB2r) agonists are potential painkillers void of psychotropic effects. Peripheral immune cells, neurons and glia express CB2r, however the involvement of CB2r from these cells in neuropathic pain remains unresolved. We explored spontaneous neuropathic pain through on-demand self-administration of the selective CB2r agonist JWH133 in wild-type and knockout mice lacking CB2r in neurons, monocytes or constitutively. Operant self-administration reflected drug-taking to alleviate spontaneous pain, nociceptive and affective manifestations. While constitutive deletion of CB2r disrupted JWH133-taking behavior, this behavior was not modified in monocyte-specific CB2r knockouts and was increased in mice defective in neuronal CB2r knockouts suggestive of increased spontaneous pain. Interestingly, CB2r-positive lymphocytes infiltrated the injured nerve and possible CB2r transfer from immune cells to neurons was found. Lymphocyte CB2r depletion also exacerbated JWH133 self-administration and inhibited antinociception. This work identifies a simultaneous activity of neuronal and lymphoid CB2r that protects against spontaneous and evoked neuropathic pain.

physiology↗