Hepatic acute phase response protects the brain from focal inflammation during postnatal window of susceptibility

Perinatal inflammation is known to contribute to neurodevelopmental diseases. Animal models of perinatal inflammation have revealed that the inflammatory response within the brain is age dependent, but the regulators of this variation remain unclear. In the adult, the peripheral acute phase response (APR) is known to be pivotal in the downstream recruitment of leukocytes to the injured brain. The relationship between perinatal brain injury and the APR has not been established. Here, we generated focal inflammation in the brain using interleukin (IL)-1β at postnatal day (P)7, P14, P21 and P56 and studied both the central nervous system (CNS) and hepatic inflammatory responses at 4 h. We found that there is a significant window of susceptibility in mice at P14, when compared to mice at P7, P21 and P56. This was reflected in increased neutrophil recruitment to the CNS, as well as an increase in blood–brain barrier permeability. To investigate phenomena underlying this window of susceptibility, we performed a dose response of IL-1β. Whilst induction of endogenous IL-1β or intercellular adhesion molecule (ICAM)-1 in the brain and induction of a hepatic APR were dose dependent, the recruitment of neutrophils and associated blood–brain barrier breakdown was inversely proportional. Furthermore, in contrast to adult animals, an additional peripheral challenge (intravenous IL-1β) reduced the degree of CNS inflammation, rather than exacerbating it. Together these results suggest a unique window of susceptibility to CNS injury, meaning that suppressing systemic inflammation after brain injury may exacerbate the damage caused, in an age-dependent manner

Modelling progressive multiple sclerosis for new treatment strategies

Multiple sclerosis (MS) is an autoimmune, demyelinating, degenerative disease of the central nervous system. Secondary progressive (SP) MS differs from relapse-remitting (RR) MS in clinical symptoms and histopathology. As disease progresses, the proportion of B cells and plasma cells increases in the brain. Moreover, meningeal tertiary lymphoid structures (TLS) are present in a large proportion of SPMS patients and are associated with more severe pathology. Treatment is available for suppressing relapses in RRMS, but no disease modifying therapy (DMT) is available for the ongoing disease worsening in SPMS. This is, in part, due to a lack of preclinical models for SPMS. There is a need for rodent models of SPMS to investigate disease mechanisms and treatment options. This thesis describes the development of two new rodent models of SPMS, characterised by glial activation, lymphocyte infiltration, demyelination, and neuronal death behind a closed blood-brain barrier (BBB). Focal MS-like lesions were induced by first immunising mice with MOG and CFA intradermally, followed by an intracranial injection with heat-killed mycobacterium tuberculosis in either the striatum or the piriform cortex. Mice were treated with anti-LINGO-1 or anti-CD20 antibodies 4 weeks after initiation of the lesion. Treatment effects on the different aspects of the focal lesions were evaluated by immunohistochemistry. MS-like lesions formed in the brains independent of injection site. However, TLS were only formed in mice with lesions in the piriform cortex. Both types of lesions continued to grow over time. Anti-LINGO-1 therapy promoted oligodendrocyte survival and reduced glial activation in the brains of these mice. Treatment with anti-CD20 decreased the extent of glial activation, significantly decreased the number of B and T lymphocytes, and reduced the size of the TLS. SPMS with and without TLS can be modelled in rodents, with lesions that continue to evolve over time behind an intact BBB. Two different treatments were shown to be effective in this model, demonstrating the potential of using anti-LINGO-1 or anti-CD20 as a DMT for SPMS.</p

Towards Predicting Basin-Wide Invertebrate Organic Biomass and Production in Marine Sediments from a Coastal Sea

<div><p>Detailed knowledge of environmental conditions is required to understand faunal production in coastal seas with topographic and hydrographic complexity. We test the hypothesis that organic biomass and production of subtidal sediment invertebrates throughout the Strait of Georgia, west coast of Canada, can be predicted by depth, substrate type and organic flux modified to reflect lability and age of material. A basin-wide database of biological, geochemical and flux data was analysed using an empirical production/biomass (P/B) model to test this hypothesis. This analysis is unique in the spatial extent and detail of P/B and concurrent environmental measurements over a temperate coastal region. Modified organic flux was the most important predictor of organic biomass and production. Depth and substrate type were secondary modifiers. Between 69–74% of variability in biomass and production could be explained by the combined environmental factors. Organisms <1 mm were important contributors to biomass and production primarily in shallow, sandy sediments, where high P/B values were found despite low organic flux. Low biomass, production, and P/B values were found in the deep, northern basin and mainland fjords, which had silty sediments, low organic flux, low biomass of organisms <1 mm, and dominance by large, slow-growing macrofauna. In the highest organic flux and biomass areas near the Fraser River discharge, production did not increase beyond moderate flux levels. Although highly productive, this area had low P/B. Clearly, food input is insufficient to explain the complex patterns in faunal production revealed here. Additional environmental factors (depth, substrate type and unmeasured factors) are important modifiers of these patterns. Potential reasons for the above patterns are explored, along with a discussion of unmeasured factors possibly responsible for unexplained (30%) variance in biomass and production. We now have the tools for basin-wide first-order estimates of sediment invertebrate production.</p> </div

Size Structure of Marine Soft-Bottom Macrobenthic Communities across Natural Habitat Gradients: Implications for Productivity and Ecosystem Function

<div><p>Size distributions of biotic assemblages are important modifiers of productivity and function in marine sediments. We investigated the distribution of proportional organic biomass among logarithmic size classes (2⁻⁶J to 2¹⁶J) in the soft-bottom macrofaunal communities of the Strait of Georgia, Salish Sea on the west coast of Canada. The study examines how size structure is influenced by 3 fundamental habitat descriptors: depth, sediment percent fines, and organic flux (modified by quality). These habitat variables are uncorrelated in this hydrographically diverse area, thus we examine their effects in combination and separately. Cluster analyses and cumulative biomass size spectra reveal clear and significant responses to each separate habitat variable. When combined, habitat factors result in three distinct assemblages: (1) communities with a high proportion of biomass in small organisms, typical of shallow areas (<10 m) with coarse sediments (<10% fines) and low accumulation of organic material (<3.0 gC/m²/yr/δ¹⁵N); (2) communities with high proportion of biomass in the largest organisms found in the Strait, typical of deep, fine sediments with high modified organic flux (>3 g C/m²/yr/δ¹⁵N) from the Fraser River; and (3) communities with biomass dominated by moderately large organisms, but lacking the smallest and largest size classes, typical of deep, fine sediments experiencing low modified organic flux (<3.0 gC/m²/yr/δ¹⁵N). The remaining assemblages had intermediate habitat types and size structures. Sediment percent fines and flux appear to elicit threshold responses in size structure, whereas depth has the most linear influence on community size structure. The ecological implications of size structure in the Strait of Georgia relative to environmental conditions, secondary production and sediment bioturbation are discussed.</p> </div

Geographic distribution in the Strait of Georgia of mean total invertebrate production, and values relative to sample modified organic carbon flux (N = 987), depth and percent sand (N = 1067).

<p>Mean values for each sample location and time are shown on figures for visual simplicity and are included in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040295#pone.0040295.s006" target="_blank">Table S5</a>. Note that the multi-factor regressions (described in results) used only data points for which all three environmental factors were available (N = 987). The overlapping red triangles represent samples from near the Fraser River discharge.</p

Geographic distribution of habitat variables for the Strait of Georgia.

<p>These include a) sediment % sand, and b) modified organic carbon flux (organic carbon flux/del 15N) including values measured from ₂₁₀Pb dated cores as well as extrapolated values for locations with biological samples lacking concurrent core data.</p

Results of BEST (BIO-ENV) routine (PRIMER-E, PlymouthMarine Laboratory) based on Spearman’s correlation between size structure resemblance matrix (Bray-Curtis similarity, standardized organic biomass data)and normalized habitat matrix (Euclidean distance).

<p>Data are otherwise not transformed.</p

Response of size structure to combined habitat factors.

<p>Samples were re-categorized based on previous cluster analyses into shallow (<10 m) and deep (≥10 m), Coarse sediments (<10% fines) and Fine sediments (≥10% fines), and low organic flux (<3 gC/m²/yr/δ¹⁵N) and high organic flux (≥3 gC/m²/yr/δ¹⁵N) and analyzed together. (<b>A</b>) Cluster analyses show relationships among habitat categories based on their community size structure. SIGTREE analyses assess which relationships are statistically significant. Asterisks indicate p<0.0001, (and thus rejection of the null hypothesis at α = 0.01 that the two groups being linked are homogeneous). P-values >0.01 are indicated above nodes. (<b>B</b>) Cumulative biomass size spectra for each habitat category show how proportional biomass accumulates across size categories of macrobenthic organisms (based on log₂ organic biomass). Horizontal lines are placed at 95% of total biomass and 50% of total pooled biomass.</p

Distribution of the proportion of total invertebrate organic biomass and production contributed by small faunal (<1 mm) organisms, relative to % sand, depth and modified organic flux (N = 65).

<p>Only % sand was significantly related to either biomass or production (r² shown on plots, p<0.01; regression coefficients described in results and data shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040295#pone.0040295.s005" target="_blank">Table S4</a>).</p

Examples of faunal production estimates from the literature, including habitat type and faunal groups analysed, illustrating ranges measured for infauna from different habitats using different estimation methods (see Cusson and Bourget [9] for a recent and more thorough global review).

++<p>classical direct measurements (respiration/cohort biomass).</p>*<p>Empirical models such as Brey <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040295#pone.0040295-Brey1" target="_blank">[7]</a>.</p>∧<p>Phylogenetic P/B conversions from literature.</p>∧∧3<p>H]-leucine incorporation.</p