Targeting GM-CSF in inflammatory and autoimmune disorders.

Granulocyte macrophage-colony stimulating factor (GM-CSF) was originally identified as a growth factor for its ability to promote the proliferation and differentiation in vitro of bone marrow progenitor cells into granulocytes and macrophages. Many preclinical studies, using GM-CSF deletion or depletion approaches, have demonstrated that GM-CSF has a wide range of biological functions, including the mediation of inflammation and pain, indicating that it can be a potential target in many inflammatory and autoimmune conditions. This review provides a brief overview of GM-CSF biology and signaling, and summarizes the findings from preclinical models of a range of inflammatory and autoimmune disorders and the latest clinical trials targeting GM-CSF or its receptor in these disorders.

IL-23p19 in osteoarthritic pain and disease.

OBJECTIVE: We have previously reported that the interleukin-23 p19 subunit (IL-23p19) is required for experimental inflammatory arthritic pain-like behavior and disease. Even though inflammation is often a characteristic feature of osteoarthritis (OA), IL-23 is not usually considered as a therapeutic target in OA. We began to explore the role of IL-23p19 in OA pain and disease utilizing mouse models of OA and patient samples. DESIGN: The role of IL-23p19 in two mouse models of OA, namely collagenase-induced OA and monosodium iodoacetate-induced OA, was investigated using gene-deficient male mice. Pain-like behavior and arthritis were assessed by relative static weight distribution and histology, respectively. In knee synovial tissues from a small cohort of human OA patients, a correlation analysis was performed between IL-23A gene expression and Oxford knee score (OKS), a validated Patient Reported Outcome Measure. RESULTS: We present evidence that i) IL-23p19 is required for the development of pain-like behavior and optimal disease, including cartilage damage and osteophyte formation, in two experimental OA models and ii) IL-23A gene expression in OA knee synovial tissues correlates with a lower OKS (r = -0.742, p = 0.0057). CONCLUSIONS: The findings support the possible targeting of IL-23 as a treatment for OA pain and disease progression.

IL-23 regulation of myeloid cell biology during inflammation.

Interleukin (IL)-23 is implicated in the pathogenesis of several inflammatory diseases and is usually linked with helper T cell (Th17) biology. However, there is some data linking IL-23 with innate immune biology in such diseases. We therefore examined the effects of IL-23p19 genetic deletion and/or neutralization on in vitro macrophage activation and in an innate immune-driven peritonitis model. We report that endogenous IL-23 was required for maximal macrophage activation by zymosan as determined by pro-inflammatory cytokine production, including a dramatic upregulation of granulocyte-colony stimulating factor (G-CSF). Furthermore, both IL-23p19 genetic deletion and neutralization in zymosan-induced peritonitis (ZIP) led to a specific reduction in the neutrophil numbers, as well as a reduction in the G-CSF levels in exudate fluids. We conclude that endogenous IL-23 can contribute significantly to macrophage activation during an inflammatory response, mostly likely via an autocrine/paracrine mechanism; of note, endogenous IL-23 can directly up-regulate macrophage G-CSF expression, which in turn is likely to contribute to the regulation of IL-23-dependent neutrophil number and function during an inflammatory response, with potential significance for IL-23 targeting particularly in neutrophil-associated inflammatory diseases.

Trans-dimensional inversion for seafloor properties for three mud depocenters on the New England shelf under dynamical oceanographic conditionsa).

This paper presents inversion results for three datasets collected on three spatially separated mud depocenters (hereafter called mud ponds) during the 2022 Seabed Characterization Experiment (SBCEX). The data considered here represent modal time-frequency (TF) dispersion as estimated from a single hydrophone. Inversion is performed using a trans-dimensional (trans-D) Bayesian inference method that jointly estimates water-column and seabed properties along with associated uncertainties. This enables successful estimation of the seafloor properties, consistent with in situ acoustic core measurements, even when the water column is dynamical and mostly unknown. A quantitative analysis is performed to (1) compare results with previous modal TF trans-D studies for one mud pond but under different oceanographic condition, and (2) inter-compare the new SBCEX22 results for the three mud ponds. Overall, the estimated mud geoacoustic properties show no significant temporal variability. Further, no significant spatial variability is found between two of the mud ponds while the estimated geoacoustic properties of the third are different. Two hypotheses, considered to be equally likely, are explored to explain this apparent spatial variability: it may be the result of actual differences in the mud properties, or the mud properties may be similar but the inversion results are driven by difference in data information content.

CCL17/TARC in autoimmunity and inflammation-not just a T-cell chemokine.

Chemokine (C-C) ligand 17 (CCL17) was first identified as thymus- and activation-regulated chemokine when it was found to be constitutively expressed in the thymus and identified as a T-cell chemokine. This chemoattractant molecule has subsequently been found at elevated levels in a range of autoimmune and inflammatory diseases, as well as in cancer. CCL17 is a C-C chemokine receptor type 4 (CCR4) ligand, with chemokine (C-C) ligand 22 being the other major ligand and, as CCR4 is highly expressed on helper T cells, CCL17 can play a role in T-cell-driven diseases, usually considered to be via its chemotactic activity on T helper 2 cells; however, given that CCR4 is also expressed by other cell types and there is elevated expression of CCL17 in many diseases, a broader CCL17 biology is suggested. In this review, we summarize the biology of CCL17, its regulation and its potential contribution to the pathogenesis of various preclinical models. Reference is made, for example, to recent literature indicating a role for CCL17 in the control of pain as part of a granulocyte macrophage-colony-stimulating factor/CCL17 pathway in lymphocyte-independent models and thus not as a T-cell chemokine. The review also discusses the potential for CCL17 to be a biomarker and a therapeutic target in human disorders.

The GM-CSF/CCL17 pathway in obesity-associated osteoarthritic pain and disease in mice.

OBJECTIVES: We have previously identified a granulocyte macrophage-colony stimulating factor (GM-CSF)/C-C motif ligand 17 (CCL17) pathway in monocytes/macrophages, in which GM-CSF regulates the formation of CCL17, and it is important for an experimental osteoarthritis (OA) model. We explore here additional OA models, including in the presence of obesity, such as a requirement for this pathway. DESIGN: The roles of GM-CSF, CCL17, CCR4, and CCL22 in various experimental OA models, including those incorporating obesity (eight-week high-fat diet), were investigated using gene-deficient male mice. Pain-like behavior and arthritis were assessed by relative static weight distribution and histology, respectively. Cell populations (flow cytometry) and cytokine messenger RNA (mRNA) expression (qPCR) in knee infrapatellar fat pad were analyzed. Human OA sera were collected for circulating CCL17 levels (ELISA) and OA knee synovial tissue for gene expression (qPCR). RESULTS: We present evidence that: i) GM-CSF, CCL17, and CCR4, but not CCL22, are required for the development of pain-like behavior and optimal disease in three experimental OA models, as well as for exacerbated OA development due to obesity, ii) obesity alone leads to spontaneous knee joint damage in a GM-CSF- and CCL17-dependent manner, and iii) in knee OA patients, early indications are that BMI correlates with a lower Oxford Knee Score (r = -0.458 and p = 0.0096), with elevated circulating CCL17 levels (r = 0.2108 and p = 0.0153) and with elevated GM-CSF and CCL17 gene expression in OA synovial tissue. CONCLUSIONS: The above findings indicate that GM-CSF, CCL17, and CCR4 are involved in obesity-associated OA development, broadening their potential as targets for possible treatments for OA.

CCL17 in Inflammation and Pain.

It has been reported that a GM-CSF→CCL17 pathway, originally identified in vitro in macrophage lineage populations, is implicated in the control of inflammatory pain, as well as arthritic pain and disease. We explore, in this study and in various inflammation models, the cellular CCL17 expression and its GM-CSF dependence as well as the function of CCL17 in inflammation and pain. This study used models allowing the convenient cell isolation from Ccl17E/+ reporter mice; it also exploited both CCL17-dependent and unique CCL17-driven inflammatory pain and arthritis models, the latter permitting a radiation chimera approach to help identify the CCL17 responding cell type(s) and the mediators downstream of CCL17 in the control of inflammation and pain. We present evidence that 1) in the particular inflammation models studied, CCL17 expression is predominantly in macrophage lineage populations and is GM-CSF dependent, 2) for its action in arthritic pain and disease development, CCL17 acts on CCR4+ non-bone marrow-derived cells, and 3) for inflammatory pain development in which a GM-CSF→CCL17 pathway appears critical, nerve growth factor, CGRP, and substance P all appear to be required.

Impacts of infauna, worm tubes, and shell hash on sediment acoustic variability and deviation from the viscous grain shearing model.

Infauna influence geoacoustic parameters in surficial marine sediments. To investigate these effects, an experiment was conducted in natural sand-silt sediment in the northern Gulf of Mexico. In situ acoustic measurements of sediment sound speed, attenuation, and shear speed were performed, and sediment cores were collected from the upper 20 cm of the seabed. Laboratory measurements of sound speed and attenuation in the cores were conducted, after which the core contents were analyzed for biological and physical properties. Since no model currently accounts for the effects of infauna, a deviation from model predictions is expected. To assess the extent of this, acoustic measurements were compared with the viscous grain shearing model from Buckingham [J. Acoust. Soc. Am. 122, 1486 (2007); J. Acoust. Soc. Am. 148, 962 (2020)], for which depth-dependent profiles of sediment porosity and mean grain size measured from the cores were used as input parameters. Comparison of acoustic results with distributions of infauna, worm tubes, and shell hash suggests biogenic impacts on acoustic variability and model accuracy are important in surficial marine sediments. The presence of infauna and worm tubes were correlated with higher variability in both sound speed and attenuation and greater deviation from the model near the sediment-water interface.

Experimental observations of a rupture induced underwater sound source.

A rupture induced underwater sound source (RIUSS) is being developed as an alternative to other impulsive sound sources commonly utilized in underwater acoustics experiments and surveys. The device is comprised of a graphite rupture disk mounted over an evacuated chamber. After the disk breaks, an inrush of water creates a high amplitude acoustic pulse. A field test was conducted to measure the acoustic output as a function of depth for a given source configuration, and high speed underwater video was simultaneously captured with an acoustic recording system to correlate the features of the acoustic output to the ensuing bubble activity.

Impacts of simulated infaunal activities on acoustic wave propagation in marine sediments.

The activities of infaunal organisms, including feeding, locomotion, and home building, alter sediment physical properties including grain size and sorting, porosity, bulk density, permeability, packing, tortuosity, and consolidation behavior. These activities are also known to affect the acoustic properties of marine sediments, although previous studies have demonstrated complicated relationships between infaunal activities and geoacoustic properties. To avoid difficulties associated with real animals, whose exact locations and activities are unknown, this work uses artificial burrows and simulates infaunal activities such as irrigation, compaction, and tube building in controlled laboratory experiments. The results show statistically significant changes in sound speed and attenuation over a frequency range of 100-400 kHz, corresponding to wavelengths on the order of the burrow diameter. The greatest effects were observed for tubes constructed of hard shells which increased the attenuation by ∼30 dB m-1 across the measurement band. These results highlight the importance of biogenic hard structures such as tubes on sound attenuation and suggest that organisms that create hard structures may be good targets for acoustic mapping of infaunal abundance and distribution.

Application of acoustical remote sensing techniques for ecosystem monitoring of a seagrass meadow.

Seagrasses provide a multitude of ecosystem services and serve as important organic carbon stores. However, seagrass habitats are declining worldwide, threatened by global climate change and regional shifts in water quality. Acoustical methods have been applied to assess changes in oxygen production of seagrass meadows since sound propagation is sensitive to the presence of bubbles, which exist both within the plant tissue and freely floating the water as byproducts of photosynthesis. This work applies acoustic remote sensing techniques to characterize two different regions of a seagrass meadow: a densely vegetated meadow of Thalassia testudinum and a sandy region sparsely populated by isolated stands of T. testudinum. A Bayesian approach is applied to estimate the posterior probability distributions of the unknown model parameters. The sensitivity of sound to the void fraction of gas present in the seagrass meadow was established by the narrow marginal probability distributions that provided distinct estimates of the void fraction between the two sites. The absolute values of the estimated void fractions are biased by limitations in the forward model, which does not capture the full complexity of the seagrass environment. Nevertheless, the results demonstrate the potential use of acoustical methods to remotely sense seagrass health and density.

Broadband sound propagation in a seagrass meadow throughout a diurnal cycle.

Acoustic propagation measurements were conducted in a Thalassia testudinum meadow in the Lower Laguna Madre, a shallow bay on the Texas Gulf of Mexico coast. A piezoelectric source transmitted frequency-modulated chirps (0.1 to 100 kHz) over a 24-h period during which oceanographic probes measured environmental parameters including dissolved oxygen and solar irradiance. Compared to a nearby less vegetated area, the received level was lower by as much as 30 dB during the early morning hours. At the peak of photosynthesis-driven bubble production in the late afternoon, an additional decrease in level of 11 dB was observed.

A comparison between directly measured and inferred wave speeds from an acoustic propagation experiment in Currituck Sound.

An acoustic propagation experiment was conducted in Currituck Sound to characterize low-frequency propagation in a very-shallow-water estuarine environment. The water column properties were homogeneous over the study area, and the emphasis of this work is on understanding the propagation effects induced by the estuarine bed. During the experiment, low-frequency sound propagation measurements of waterborne sound and interface waves were acquired, and direct measurements of the compressional and shear wave properties were obtained at high frequencies. The propagation data consist of signals from a Combustive Sound Source recorded on bottom mounted geophones and a vertical line array of hydrophones. A statistical inference method was applied to obtain an estimate of the sediment compressional and shear wave speed profiles as a function of depth within the estuarine bed. The direct measurements were obtained in situ by inserting probes 30 cm into the sediment. Sediment acoustics models were fit to the high-frequency in situ data to enable comparison with the inferred low-frequency wave speeds. Overall, good agreement was found between the directly measured and inferred wave speeds for both the compressional and shear wave data.

Attenuation of low-frequency underwater sound using an array of air-filled balloons and comparison to effective medium theory.

The ultimate goal of this work is to accurately predict the attenuation through a collection of large (on the order of 10-cm-radius) tethered encapsulated bubbles used in underwater noise abatement systems. Measurements of underwater sound attenuation were performed during a set of lake experiments, where a low-frequency compact electromechanical sound source was surrounded by different arrays of encapsulated bubbles with various individual bubbles sizes and void fractions. The measurements were compared with an existing predictive model [Church, J. Acoust. Soc. Am. 97, 1510-1521 (1995)] of the dispersion relation for linear propagation in liquid containing encapsulated bubbles. Although the model was originally intended to describe ultrasound contrast agents, it is evaluated here for large bubbles, and hence low frequencies, as a design tool for future underwater noise abatement systems, and there is good quantitative agreement between the observations and the model.

Radiation damping of, and scattering from, an arbitrarily shaped bubble.

The work by Strasberg on small volume oscillations of bubbles with arbitrary shape [J. Acoust. Soc. Am. 25, 536-537 (1953)] is here extended to include the effects of radiation damping. An expression for the far-field scattering amplitude from an arbitrarily shaped bubble is given in terms of a quantity that is mathematically equivalent to the electrostatic capacitance of the bubble shape. This general approach is then applied to prolate and oblate spheroidal geometries, for which simple analytic expressions are available for the electrostatic capacitance, and the resulting far-field scattering amplitudes are compared to previous work in the literature.

Sound speed and attenuation measurements within a seagrass meadow from the water column into the seabed.

In situ measurements of sound speed and attenuation at 50 kHz were conducted in a Thalassia testudium meadow. Measurements were obtained at discrete depths in the water column, in the seagrass canopy, and in the sediment beneath the seagrass. Measurements were also obtained in bare sediment located a few meters away. Sediment biomass abundance was measured from cores collected at each site. Even though the measurements were obtained in the dormant season (winter), significant differences in sound speed and attenuation were observed in the sediment beneath the seagrass bed compared to the bare sediment.

Passive Underwater Noise Attenuation Using Large Encapsulated Air Bubbles.

Measurements demonstrating low-frequency underwater sound attenuation using arrays of large, tethered, stationary encapsulated bubbles to surround a sound source were compared with various effective medium models for the acoustic dispersion relationship in bubbly liquids. Good agreement was observed between measurements for the large bubbles (on the order of 10 cm) at frequencies below 1 kHz and a model originally intended to describe the acoustic behavior of ultrasound contrast agents. The primary goal is to use the model for designing encapsulated-bubble-based underwater noise abatement systems and to reduce uncertainty in system performance.

Examining the effects of microstructure on geoacoustic parameters in fine-grained sediments.

This paper presents a set of controlled laboratory experiments designed to develop a basis for understanding the relationship between microscopic and macroscopic properties of fine-grained sediments. Two samples of kaolinite platelets were selected for this study, and effects of sediment microstructure on geoacoustic properties are deduced from a comparison of the measured properties. To provide additional interpretation of the acoustic measurements, compressional and shear wave properties are compared to predicted values from sediment-acoustic models. First, the shear wave speed was compared to predictions from card-house theory, a model with an electrochemical basis that incorporates the aggregation of clay platelets. The wave speed predicted by card-house theory showed good agreement with the measured wave speeds for the mud sample made up of card-house flocs. Next, viscous grain shearing theory, which treats unconsolidated sediments as a two-phase medium with internal losses arising from grain-to-grain contacts, was applied to predict the frequency dispersion of all four geoacoustic parameters. Overall, good agreement between the measurements and values calculated by viscous grain shearing theory was observed for both samples of mud.

In situ measurements of sediment acoustic properties in Currituck Sound and comparison to models.

In situ measurements of compressional and shear wave speed and attenuation were collected 30 cm below the water-sediment interface in Currituck Sound, North Carolina at two field locations having distinctly different sediment types: medium-to-fine-grained sand and fine-grained sand with approximately 10% mud content. Shear wave measurements were performed with bimorph transducers to generate and receive horizontally polarized shear waves in the 300 Hz to 1 kHz band, and compressional wave measurements were performed using hydrophones operated in the 5 kHz to 100 kHz band. Sediment samples were collected at both measurement sites and later analyzed in the laboratory to characterize the sediment grain size distribution for each field location. Compressional and shear wave speed and attenuation were estimated from the acoustic measurements, and preliminary comparisons to the extended Biot model by Chotiros and Isakson [J. Acoust. Soc. 135, 3264-3279 (2014)] and the viscous grain-shearing theory by Buckingham [J. Acoust. Soc. 136, 2478-2488 (2014)] were performed.

Attenuation of standing waves in a large water tank using arrays of large tethered encapsulated bubbles.

The use of bubble resonance effects to attenuate low-frequency underwater sound was investigated experimentally in a large water tank. A compact electromechanical sound source was used to excite standing wave fields at frequencies ranging between 50 and 200 Hz in the tank. The source was then surrounded by a stationary array of tethered encapsulated air bubbles, and reduction in standing wave amplitude by as much as 26 dB was observed. The bubbles consisted of either thin-shelled latex balloons with approximately 5 cm radii or thicker-shelled vinyl boat fenders with 6.9 cm radii. The effects of changing the material and thickness of the bubble shells were found to be in qualitative agreement with predictions from Church's model for sound propagation in a liquid containing encapsulated bubbles [J. Acoust. Soc. Am. 97, 1510-1521 (1995)]. Although demonstrated here for low frequency noise abatement within a tank, which is useful for quieting acoustic test facilities and large tanks used for marine life husbandry, the eventual aim of this work is to use stationary arrays of large tethered encapsulated bubbles to abate low frequency underwater noise from anthropogenic sources in the marine environment.