Biology subjects

Dalli, J.

Publications and source records attributed to Dalli, J..

8 recordsLinked to original sources

bioRxiv2026

Erythroblast-derived mediators program neutrophil development and function

Granulopoiesis is a tightly regulated process encompassing the production, maturation, and release of neutrophils in the bone marrow, ensuring their optimal physiological contribution to host defence. The mechanisms that maintain a balanced regulation of neutrophil effector functions during this process remain incompletely understood. Here, we identify bone marrow-resident erythroblasts as a key source of specialized pro- resolving mediators (SPMs) and show that they imprint neutrophil development and function. Terminally differentiating erythroblasts highly express the key SPM biosynthetic enzyme 12/15-lipoxygenase (Alox15) and accordingly generate several SPMs, including n-3 docosapentaenoic acid-derived Resolvin D5 (RvD5n-3 DPA). Conditional erythroblast-specific depletion of Alox15 decreased bone marrow SPM levels and caused altered neutrophil phenotypes including augmented release of reactive oxygen species and neutrophil extracellular traps and increased migration to chemotactic stimuli, leading to increased neutrophil sequestration in peripheral organs and concomitant neutropenia. Mice with erythroblast-specific Alox15 depletion displayed impaired bacterial clearance in experimental peritonitis and increased severity in DSS-colitis. Aberrant neutrophil phenotypes were rectified by the reconstitution of RvD5n-3 DPA and were largely recapitulated by the specific depletion of the SPM receptor Gpr101 in bone marrow macrophages, but not in neutrophil precursors, suggesting the involvement of the macrophage niche in mediating the SPM effects on granulopoiesis. Our findings establish a central role for erythroblasts and their SPM production in instructing granulopoiesis for balanced functional neutrophil responses. Key PointsErythroblasts are a source of Alox15-dependent SPMs that regulate BM erythroblastic island integrity and neutrophil maturation and function Loss of erythroblast Alox15 disrupts neutrophil development and function, defects that are restored add-back of RvD5n-3 DPA.

immunology↗

bioRxiv2025

Phospholipid esters from herring roe promotes SPM biosynthesis in human monocyte-derived macrophages and a keratinocyte/fibroblast co-culture with implications for the treatment of psoriasis

Psoriasis is a chronic immune-mediated inflammatory disease (IMID) affecting the skin presenting with both local and systemic inflammation as part of its pathophysiology. An oil rich in phospholipids extracted from herring roe has been shown to have immunomodulatory properties and to improve clinical symptoms and impact inflammatory cytokine pathways in psoriasis in a clinical trial. The lipidic nature of herring roe oil (HRO) and its high content of polyunsaturated fatty acids suggests involvement of lipid mediator pathways for the observed alleviation of psoriatic inflammation. Of particular interest is the super-family of lipid mediators termed specialized pro-resolving mediators (SPMs), due to their involvement in resolution of inflammation and subsequent return to homeostasis. We therefore explored the influence of HRO and its phospholipids on lipid mediator and SPM biosynthesis in IFN-{gamma} and LPS-stimulated human monocyte-derived macrophages and an IL-17A-stimulated keratinocyte/fibroblast co-culture. Lipid mediators including SPMs were quantified from cell supernatants using a validated LC-MS/MS protocol. In these experiments we observed broad SPM biosynthesis with dominant upregulation of RvE2 and RvE3 in both cell systems and upregulation of DHA-derived SPMs such as RvD2 and PDX. Observations of PCTR2 in macrophage cell supernatants also indicate activation of reparative pathways upon treatment with HRO. In conclusion, we observed promotion of SPM biosynthesis associated with a shift towards a protective and possibly reparative macrophage phenotype as well as promotion of biosynthesis of pro-resolving lipid mediators in a skin cell co-culture, thus demonstrating a possible mechanism for resolution of inflammation in the skin niche using HRO.

biochemistry↗

bioRxiv2025

Formyl-peptide receptor type 2 activation mitigates secondary organ damage in inflammatory arthritis

Rheumatoid arthritis (RA) is associated with heart and lung dysfunction. Current therapies fail to attenuate such complications. Here, we identify formyl-peptide receptor type 2 (FPR2) as therapeutic target to treat heart and lung dysfunction associated with inflammatory arthritis. Arthritic mice on high levels of dietary homocysteine develop cardiac diastolic dysfunction and reduced lung compliance, mirroring two comorbidities in RA. Therapeutic administration of a small molecule FPR2 agonist (BMS986235) to hyper-homocysteine arthritic mice prevented diastolic dysfunction (monitored by echocardiography) and restored lung compliance. These tissue-specific effects were secondary to reduced neutrophil infiltration, modulation of fibroblast activation and phenotype (in the heart) and attenuation of monocyte and macrophage numbers (in the lung). A dual FPR1/2 agonist (compound 43) failed to prevent the reduction in lung compliance of arthritic mice and promoted accumulation of inflammatory monocytes and pro-fibrotic macrophages in lung parenchyma. This cellular response lies downstream of FPR1-mediated potentiation of CCL2-dependent monocyte chemotaxis and activation. This finding supports therapeutic development of selective FPR2 agonists to mitigate two impactful comorbidities associated with inflammatory arthritides.

pharmacology and toxicology↗

bioRxiv2025

Pre-stimulation of Precision-Cut bovine udder slices with zymosan before LPS exposure indicates indicators for trained immunity

Mastitis in cattle poses a significant health challenge and results in substantial economic losses for the dairy industry. This study aimed to establish precision-cut bovine udder slices (PCBUS) as an in vitro model to explore the potential of stimulating trained immunity in the udder. The goal was to investigate whether this approach could influence the early pathophysiological processes of mastitis and pave the way for developing new therapeutic strategies for udder inflammation in future research. PCBUS remained viable in culture for up to two weeks. When stimulated with E. coli-derived lipopolysaccharide (LPS), zymosan (an inducer of trained immunity), or pre-incubated with zymosan followed by LPS stimulation, the slices exhibited distinct responses in terms of pro-inflammatory cytokine production and lipid mediator profiles. Additionally, cytokine production was influenced by the presence or absence of fetal calf serum (FCS), highlighting the potential limitations of FCS in in vitro studies. While the current experimental setup did not definitively confirm the induction of trained immunity in the bovine udder, it validated the utility of PCBUS as a robust in vitro model for studying bovine udder inflammation. This model offers a promising platform for developing innovative mastitis treatments, particularly given the growing concern over antimicrobial resistance. It also provides a valuable tool for advancing our understanding of immune responses in the bovine udder. By adapting the precision-cut tissue slice technique to bovine udders, this model enables extensive research into new therapeutic approaches and supports basic research efforts to characterize complex pathophysiological processes associated with mastitis.

immunology↗

bioRxiv2023

Mistakes in the re-analysis of lipidomic data obtained from a human model of resolving inflammation lead to erroneous conclusions.

Recent years have seen an increased interest in the biology of specialized pro-resolving lipid mediators (SPM) with many investigators evaluating both their endogenous production as well as their biological and pharmacological properties. This increased interest has led to a rapid evolution in our understanding of both the biological and pharmacological activities of these mediators with their endogenous formation and biological activities being documented in a wide range of species that spans the evolutionary tree including fish, planaria and humans. Despite this plethora of evidence in a recent article Homer and colleagues claim that the reanalysis of a published dataset - partly originating from our laboratory - demonstrates that these molecules are absent in human blister exudates, contrary to the evidence published earlier. Based on their observations these Authors conclude that SPM are not relevant to human resolution biology. In this manuscript a reanalysed the dataset using unbiased methodologies and criteria that align with those recently proposed by the UK Consortium on Metabolic Phenotyping was performed together with the re-analysis of the dataset using criteria described by Homer and colleagues. Results from this re-analysis confirmed presence of SPM in human blister exudates and that the methodologies employed for quantitation of these molecules are robust. We also discuss how the results obtained in the article published by Homer and colleagues present several points of concern including the use of employ an arbitrary cut-off value to assign the noise for all the transitions used that does not take into consideration the fluctuation of the signal in each transition and therefore is not truly representative of the background signal. The use of different transitions to those employed in the original analyses and misreporting of findings based on the criteria employed. In conclusion the evidence presented herein demonstrates that correct application of rigorous criteria accepted by the community is essential in ensuring accurate identification of mediators and avoid blatant mistakes which can impact on the scientific development of the field.

immunology↗

bioRxiv2022

Evidence for the presence and diagnostic utility of SPM in human peripheral blood

We thank ODonnell et al, for their comments on our contribution and are grateful to be afforded this opportunity to formally respond to their critique24. We are surprised by the authors assertion relating to the biological relevance of SPM because a simple literature search for related terms such as resolvin in PubMed yields an abundance (>1,420 publications) of evidence supporting the potent biological activities and the diagnostic potential of some of these mediators. Several co-authors of the ODonnells et al manuscript, have published on the resolvins and SPMs, including some publications within recent weeks. Importantly, ODonnell et al, misreport as well as mis-apply criteria for peak identification reported in the Gomez et al, publication which lead to the flawed analysis they performed. In this response therefore, we provide a step-by-step clarification of the methodologies used in Gomez et al, and a side-by-side comparison of the underlying data to clarify any confusion. We also demonstrate that using the orthogonal criteria discussed by ODonnell et al, we obtain essentially identical results thus providing additional validation of our techniques and support the conclusions.

immunology↗

bioRxiv2019

Pro-Resolving Mediator Profiles And 5-Lipoxygenase Activity In Cerebrospinal Fluid Correlate with Disease Severity and Outcome in Adults with Tuberculous Meningitis

Tuberculous meningitis (TBM) is the most lethal form of tuberculosis infection, characterized by a dysregulated immune response that frequently leads to neurological injury and death despite the best available treatment. The mechanisms driving the inflammatory response in TBM are not well understood. To gain insights into these mechanisms we used a lipid mediator profiling approach to investigate the regulation of a novel group of host protective mediators, termed specialized pro-resolving mediators (SPM), in the cerebrospinal fluid (CSF) of adults with TBM enrolled into a randomised placebo-controlled trial of adjunctive aspirin treatment. We found distinct lipid mediator profiles with increasing disease severity, changes that were linked with an upregulation of inflammatory eicosanoids in patients with severe TBM and a decrease in the production of a number of 5-lipoxygenase (ALOX5)-derived SPM. CSF pro-resolving mediator concentrations were also associated with 80-day survival. In survivors, we found a significant increase in pro-resolving mediator concentrations, including the ALOX5-derived resolvin (Rv)T2, RvT4 and 15-epi-Lipoxin (LX)B4, compared to those who died. Aspirin administration increased the ratio of pro-resolving to pro-inflammatory mediators decreasing the concentrations of the prothrombic mediator TxA2, changes that were linked with early reductions in brain infarcts and deaths. Together, these findings identify a CSF SPM signature that is associated with disease severity and 80-day mortality in TBM. Furthermore, the therapeutic manipulation of the ratio between pro-resolving mediators and pro-inflammatory/thrombogenic mediators in the CSF, by aspirin for example, offers a novel treatment strategy to reduce the morbidity and mortality caused by TBM.\n\nAuthors SummaryInfections of the brain and the meninges by Mycobacterium tuberculosis (M. tb) lead to severe inflammation and are associated with poor outcomes. The mechanisms leading to this disease remain poorly defined. Herein, we investigated how M. tb infection regulates the concentrations of specialized pro-resolving mediators that are central in controlling the bodys ability to clear infections. In these investigations, we found that disease survival was linked with increased concentrations of a number of these protective molecules including resolvins and lipoxins. Treatment of M. tb-infected patients with aspirin decreased the production of the immunosuppressive and thrombogenic mediator thromboxane A2 improving the balance between protective and inflammatory molecules. Of note, these changes were linked with reduced disease severity and improved survival. Therefore, the present findings suggest a previously unappreciated role for pro-resolving mediators in TBM pathogenesis.

immunology↗

bioRxiv2019

Proresolving mediators LXB4 and RvE1 regulate inflammation in stromal cells from patients with shoulder tendon tears

Tendon stromal cells isolated from patients with chronic shoulder rotator-cuff tendon tears show dysregulated resolution responses. Current therapies do not address the biological processes concerned with persistent tendon inflammation, therefore new therapeutic approaches targeting tendon stromal cells are required. We determined if two specialised pro-resolving mediators (SPM) LXB4 and RvE1, modulated the bioactive lipid mediator (LM) profiles of IL-1{beta} stimulated tendon cells derived from patients with shoulder tendon tears and healthy volunteers. We also determined if LXB4/RvE1 treatments moderated the pro-inflammatory phenotype of tendon tear stromal cells. Incubation of IL-1{beta} treated patient derived tendon cells in LXB4/RvE1 upregulated concentrations of SPM. RvE1 treatment specifically increased 15-epi-LXB4 and regulated PGF2. LXB4 or RvE1 also induced expression of the SPM biosynthetic enzymes 12-liopxygeanse (ALOX12), and ALOX15. RvE1 treatment upregulated proresolving receptor ERV1 compared to vehicle treated cells. Incubation in LXB4 or RvE1 moderated the proinflammatory phenotype of patient derived tendon tear cells, regulating markers of tendon inflammation, including Podoplanin, CD90, STAT-1 and IL-6. These treatments also suppressed JNK1/2/3, Lyn, STAT-3 and STAT-6 and induced p70s6kinase phospho-kinase signalling. LXB4 and RvE1 counter-regulate inflammatory processes in tendon stromal cells, supporting the role of these molecules as potential therapeutics to resolve tendon inflammation.

cell biology↗