Biology subjects

Konkel, J. E.

Publications and source records attributed to Konkel, J. E..

6 recordsLinked to original sources

bioRxiv2025

Specific deletion of interleukin-1 beta in microglia improves acute outcome and modulates neurogenesis after ischemic stroke

Interleukin-1 (IL-1) signaling is a major driver of post-ischemic neuroinflammation, yet the cell- and isoform-specific roles of the two major IL-1 receptor type 1 agonists, IL-1 and IL-1{beta}, remain incompletely defined in the context of stroke. Microglia rapidly express IL-1 after cerebral ischemia, whereas IL-1{beta} expression is delayed and restricted to a small subset of microglia and infiltrating immune cells. Here, we investigated for the first time the specific contribution of microglial-derived IL-1{beta} to acute injury and post-stroke neurorepair after transient middle cerebral artery occlusion in male and female mice, through microglial-specific tamoxifen-inducible Cre-loxP-mediated recombination. Deletion of microglial IL-1{beta} improved acute neurological outcome, reduced neutrophil accumulation in the ischemic brain and dampened systemic inflammatory cytokines. These effects were most evident during the acute phase and in female in mice. In contrast, long-term functional recovery was largely unaffected. However, microglial IL-1{beta} deletion differentially regulated post-stroke neurogenesis, enhancing subventricular zone neurogenic responses and ectopic neuroblast migration while limiting hippocampal neurogenesis. Together, these findings identify microglial IL-1{beta} as a key amplifier of early inflammatory injury after stroke, exerting region-specific effects on neurogenic niches, and highlight distinct, non-redundant roles for microglial IL-1 isoforms in ischemic brain injury and repair.

neuroscience↗

bioRxiv2025

Migratory dermal gamma delta T cells determine the balance between lung immunity and tissue damage during Nippostrongylus brasiliensis infection

Many helminth parasites migrate through multiple host organs during infection but how immune responses are relayed across these tissues is still poorly understood. To investigate the cellular and molecular aspects of inter-tissue communication during infection we established a percutaneous infection model with the tissue-migrating nematode Nippostrongylus brasiliensis. High-dimension profiling of the initial cutaneous immune response revealed that dermal {gamma}{delta} T cells become activated via an IL-1R-dependent mechanism, engage cell motility-associated transcriptional pathways and leave the skin after parasite invasion. Chemical and genetic inhibition of leukocyte migration prevents the accumulation of IL-17-producing {gamma}{delta} T cells in the lungs. Notably, bypassing the skin phase of infection, and therefore preventing dermal {gamma}{delta} T cell migration, dampens the increase in early IL-17 production in the lungs, and, instead, leads to enhanced IFN-{gamma} responses together with increased lung damage. Collectively, our data highlights a critical skin-lung axis regulating host-parasite interactions and safeguarding lung health.

immunology↗

bioRxiv2023

Mgl2+ cDC2s coordinate fungal allergic airway type 2, but not type 17, inflammation.

Fungal spores are abundant in the environment and a major cause of asthma. Originally characterised as a type 2 inflammatory disease, allergic airway inflammation that underpins asthma can also involve type 17 inflammation, which can exacerbate disease causing failure of treatments tailored to inhibit type 2 factors. However, the mechanisms that determine the host response to fungi, which can trigger both type 2 and type 17 inflammation in allergic airway disease, remain unclear. We found that CD11c+ DCs and CD4+ T cells are essential for development of both type 2 and type 17 airway inflammation in mice when repeatedly exposed to inhaled spores. Single cell RNA-sequencing enabled the development of multi-parameter cytometry that identified allergic inflammation dramatically altered the proportion of numerous DC clusters in the lung, but that only two of these (Mgl2+ cDC2s and CCR7+ DCs) migrated to the dLNs. Targeted removal of several DC subsets revealed that only Mgl2+ cDC2 depletion dramatically reduced type 2, but not type 17, anti-fungal allergic airway inflammation. These data highlight distinct DC subsets are potential therapeutic targets for the treatment of pulmonary fungal disease.

immunology↗

bioRxiv2023

CD163 and Tim-4 identify resident intestinal macrophages across sub-tissular regions that are spatially regulated by TGF-β

In bodily organs, macrophages are localised in poorly understood tissular and sub-tissular niches associated with defined macrophage ontogeny and activity. In the intestine, a paradigm is emerging that long-lived macrophages are dominantly present in the muscular layer, while highly monocyte-replenished populations are found in the lamina propria beneath the epithelial barrier. Whether longevity is restricted in such a simplified manner has not been well explored. Moreover, the impact of specific gut-associated factors on long-lived macrophage functionality and niche occupancy is unknown. We generated sc-RNA-Seq data from wild-type and Ccr2-/- mice to identify phenotypic features of long-lived macrophage populations in distinct intestinal niches and identified CD163 as a useful marker to distinguish submucosal/muscularis (S/M) from lamina propria (LP) macrophages. Challenging the emerging paradigm, long-lived macrophages, identified by Tim-4 expression, were found in the LP and S/M. Long-lived LP macrophages are restrained in their response to proinflammatory stimulation compared to short-lived populations in the same location, and to the long-lived population within the S/M. Employing a novel Timd4creTgfbr2fl/fl mouse line we demonstrate distinct functions of TGF-{beta} on long-lived macrophages in these two compartments. Importantly, in Timd4creTgfbr2fl/fl mice, zonation of CD163+ macrophages in the S/M was lost, suggesting TGF-{beta} plays an unappreciated role in positioning of macrophages in the tissue. These data highlight the importance of considering ontogeny and niche when assessing the action of key intestinal regulatory signals.

immunology↗

bioRxiv2022

Distinct eosinophil subsets are modulated by agonists of the commensal-metabolite and vitamin B3 receptor GPR109A during allergic-type inflammation

Eosinophils are key contributors to allergic pathology, however, increasingly eosinophils are described to have important roles in organ health and immunoregulation. Factors that impact these diverse functions of eosinophils are not understood. Here we show in allergic-type lung inflammation, metabolically distinct populations of eosinophils can be identified based on expression of Siglec-F (Siglec-Fhi and Siglec-Fint). Notably, the lung Siglec-Fhi population was responsive to the commensal microbiome, expressing the short-chain fatty acid receptor GPR109A. Animals deficient in GPR109A displayed augmented eosinophilia during allergy. Moreover, transferred GPR109A-deficient eosinophils released more eosinophil peroxidase than controls. Treatment with butyrate or vitamin B3, both GPR109A ligands, reduced Siglec-Fhi eosinophil frequency and activation, which was associated with apoptosis of Siglec-Fhi eosinophils. These findings identify GPR109A as an unappreciated regulator of glycolytic Siglec-Fhi eosinophils, raising the possibility of depleting pathological eosinophil populations in disease states while sparing those with homeostatic functions.

immunology↗

bioRxiv2021

Genotype and Th2 cells control monocyte to tissue resident macrophage differentiation during nematode infection of the pleural cavity

The recent revolution in tissue-resident macrophage biology has resulted largely from murine studies performed in the C57BL/6 strain. Here, we provide a comprehensive analysis of immune cells in the pleural cavity using both C57BL/6 and BALB/c mice. Unlike C57BL/6 mice, naive tissue-resident Large Cavity Macrophages (LCM) of BALB/c mice failed to fully implement the tissue residency program. Following infection with a pleural-dwelling nematode these pre-existing differences were accentuated with LCM expansion occurring in C57BL/6 but not BALB/c mice. While infection drove monocyte recruitment in both strains, only in C57BL/6 mice were monocytes able to efficiently integrate into the resident pool. Monocyte to macrophage conversion required both T cells and IL-4R signalling. Host genetics are therefore a key influence on tissue resident macrophage biology, and during nematode infection Th2 cells control the differentiation pathway of tissue resident macrophages. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/472661v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@bba5e1org.highwire.dtl.DTLVardef@1876aa4org.highwire.dtl.DTLVardef@16a6b1corg.highwire.dtl.DTLVardef@19e18b6_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗