Biology subjects

McCulloch, L.

Publications and source records attributed to McCulloch, L..

5 recordsLinked to original sources

bioRxiv2025

DYNAMIC CHANGES TO THE INTESTINAL ENVIRONMENT OCCUR THROUGHOUT RECOVERY FROM EXPERIMENTAL ISCHAEMIC STROKE

Stroke survivors experience a plethora of complications during recovery, including gastrointestinal symptoms. Intestinal dysfunction is reported to occur rapidly following stroke in both humans and animal models and alterations such as reduced barrier integrity, lymphocyte loss, and an altered microbiota have been suggested to contribute to poor neurological outcomes. Despite the persistence of gastrointestinal symptoms in many stroke survivors, how the intestinal environment changes over the course of stroke recovery remains poorly understood. Here, we use an experimental model of ischemic stroke to profile the gastrointestinal tract over a three month period of recovery.We have shown that experimental stroke leads to structural alterations to the colon, impaired transit times and an altered bacterial community composition. No impairments to barrier function were detected at any time point and transit times recover within 2 weeks post stroke. In contrast, structural and bacterial community alterations remain up to 3 months post stroke and are accompanied by abnormalities that develop only during chronic recovery, such as altered antibody coating of bacteria. These results suggest that the gastrointestinal system is dynamically altered over the course of experimental stroke recovery and that certain defects persist chronically after stroke.

immunology↗

bioRxiv2022

Cystatin F (Cst7) drives sex-dependent changes in microglia in an amyloid-driven model of Alzheimer's Disease

Microglial endolysosomal (dys)function is strongly implicated in neurodegeneration. Transcriptomic studies show that a microglial state characterised by a set of genes involved in endolysosomal function is induced in both mouse Alzheimers Disease (AD) models and in human AD brain and that the onset of this state is emphasized in females. Cst7 (encoding protein Cystatin F) is among the most highly upregulated genes in these microglia. However, despite such striking and robust upregulation, the sex-specific function of Cst7 in neurodegenerative disease is not understood. Here, we crossed Cst7-/- mice with the AppNL-G-F mouse to test the role of Cst7 in a model of amyloid-driven AD. Surprisingly, we found that Cst7 plays a sexually dimorphic role regulating microglia in this model. In females, Cst7-deficient microglia had greater endolysosomal gene expression, lysosomal burden, and amyloid beta (A{beta}) burden in vivo and were more phagocytic in vitro. However, in males, Cst7-deficient microglia were less inflammatory and had a reduction in lysosomal burden but had no change in A{beta} burden. This study has important implications for AD research, confirming the functional role of a gene which is commonly upregulated in disease models, but also raising crucial questions on sexual dimorphism in neurodegenerative disease and the interplay between endolysosomal and inflammatory pathways in AD pathology.

neuroscience↗

bioRxiv2021

Treatment with IgM-enriched intravenous immunoglobulins (IgM-IVIg) enhances clearance of stroke-associated bacterial lung infection

Post-stroke infection is a common complication of stroke that is associated with increased mortality and morbidity. We previously found that experimental stroke induces an ablation of multiple sub-populations of B cells and reduced levels of IgM antibody that coincide with the development of spontaneous bacterial pneumonia. Reduced circulating IgM concentrations were also observed in acute stroke patients. The loss of IgM antibody after stroke could be an important determinant of infection susceptibility and highlights this pathway as an important target for intervention. We treated mice with a low (replacement), dose of IgM-enriched intravenous immunoglobulin (IgM-IVIg) prior to and 24 h after experimental stroke induced by middle cerebral artery occlusion (MCAO) or sham surgery, then recovered mice for 2 d or 5 d. The effect of treatment on lung bacterial burden, lung pathology, brain infarct volume, antibody levels and both lung and systemic cellular and cytokine immune profiles was determined. Treatment with IgM-IVIg enhanced bacterial clearance from the lung after MCAO and improved pathology but did not impact infarct volume. IgM-IVIg treatment induced immunomodulatory effects systemically including rescue of splenic plasma B cell numbers and endogenous mouse IgM and IgA circulating immunoglobulin concentrations that were reduced by MCAO, and treatment also reduced concentrations of pro-inflammatory cytokines in the lung. The effects of MCAO and IgM-IVIg treatment on the immune system were tissue specific as no impact on B cells or mouse immunoglobulins were found within the lung. However, the presence of human immunoglobulins from the IgM-IVIg treatment led to increased total lung immunoglobulin concentration. IgM-IVIg treatment did not increase the number of lung mononuclear phagocytes or directly modulate macrophage phagocytic capacity but enhanced their capability to phagocytose Staphylococcus aureus bioparticles in vitro by increasing opsonisation. Low dose IgM-IVIg contributes to increased clearance of spontaneous lung bacteria after MCAO likely via increasing availability of antibody in the lung to enhance phagocytic activity. Immunomodulatory effects of IgM-IVIg treatment, including reduced pro-inflammatory cytokine production, may also contribute to reduced levels of damage in the lung after MCAO. IgM-IVIg shows promise as an antibacterial and immunomodulatory agent to use in the treatment of post-stroke infection. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/472965v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1c8684forg.highwire.dtl.DTLVardef@384688org.highwire.dtl.DTLVardef@9eb7f7org.highwire.dtl.DTLVardef@3fe58e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2019

Promiscuous receptor activation mediates glucagonostatic effects of GLP-1(9-36) and GLP-1(7-36)

The incretin hormone glucagon-like peptide 1(7-36) (GLP-1(7-36)) stimulates insulin and inhibits glucagon secretion. The mechanisms by which GLP-1 suppresses glucagon release are unclear as glucagon-secreting -cells express GLP-1 receptors (GLP-1Rs) at very low levels. Here, we examine the underlying mechanisms. We find that both GLP-1(7-36) and its degradation product GLP-1(9-36) inhibit glucagon secretion at physiological (pM) concentrations. Whereas the effect of GLP-1(7-36) is sensitive to PKA inhibition, GLP-1(9-36) exerts its effect by a PKA-independent mechanism sensitive to pretreatment with pertussis. The glucagonostatic effects of both GLP-1(7-36) and (9-36) are retained in islets from Glp1r knockout mice but only GLP-1(9-36) remains glucagonostatic in the presence of the DPP-4 (the peptidase catalyzing the formation of GLP-1(9-36)) inhibitor sitagliptin. Glucagon receptor (GCGR) antagonism specifically prevents the inhibitory effects of GLP-1(9-36) whilst not affecting that of GLP-1(7-36). We conclude that GLP-1(7-36) and GLP-1(9-36) regulate glucagon secretion via interaction with GLP-1R and GCGR, respectively. HighlightsO_LIGLP-1(7-36) and GLP-1(9-36) inhibit glucagon secretion from alpha-cells C_LIO_LIGLP-1(7-36) and (9-36) retain glucagonostatic effect in Glp1r-/- islets C_LIO_LIGLP-1(7-36) and (9-36) activate distinct signal transduction mechanisms C_LIO_LIGLP-1(7-36) acts via GLP-1R and GLP-1(9-36) via GCGR C_LI

molecular biology↗

bioRxiv2019

Interleukin-1 receptor antagonist treatment in acute ischaemic stroke does not alter systemic markers of anti-microbial defence

AimBlockade of the cytokine interleukin-1 (IL-1) with IL-1 receptor antagonist (IL-1Ra) is a candidate treatment for stroke entering phase II/III trials, which acts by inhibiting harmful inflammatory responses. Infection is a common complication after stroke that significantly worsens outcome and is related to stroke-induced deficits in systemic immune function thought to be mediated by the sympathetic nervous system. Therefore, immunomodulatory treatments for stroke, such as IL-1Ra, carry a risk of aggravating stroke-associated infection. Our primary objective was to determine if factors associated with antibody-mediated antibacterial defences were further compromised in patients treated with IL-1Ra after stroke. MethodsWe assessed plasma concentrations of immunoglobulin isotypes and complement components in stroke patients treated with IL-1Ra or placebo and untreated non-stroke controls using multiplex protein assays. Activation of the SNS was determined by measuring noradrenaline, a major SNS mediator. ResultsThere were significantly lower plasma concentrations of IgM, IgA, IgG1 and IgG4 in stroke-patients compared to non-stroke controls, however there were no differences between stroke patients treated with placebo or IL-1Ra. Concentrations of complement components associated with the classical pathway were increased and those associated with the alternative pathways decreased in stroke patients, neither being affected by treatment with IL-1Ra. Noradrenaline concentrations were increased after stroke in both placebo and IL-1Ra-treated stroke patients compared to non-stroke controls. ConclusionThese data show treatment with IL-1Ra after stroke does not alter circulating immunoglobulin and complement concentrations, and is therefore unlikely to further aggravate stroke-associated infection susceptibility through reduced availability of these key anti-microbial mediators.

immunology↗