Prevalence and treatment patterns of adult atopic dermatitis in the UK Clinical Practice Research Datalink.

The prevalence of active atopic dermatitis (AD) in adults in the UK according to disease severity shows variability. This study evaluated disease prevalence and treatment patterns among the adult UK population with AD. Data were obtained from the Clinical Practice Research Datalink (CPRD) database. Adults with active AD were identified by an AD-related prescription or general practitioner visit within the same calendar year. Prevalence was defined as the number of patients with active AD on 1 January of each year as a percentage of the number of adults in the CPRD population on that date. Moderate-to-severe disease was classified as either referral to a specialist or prescription(s) for topical calcineurin inhibitors, phototherapy, or systemic treatment. Patient characteristics and treatment and referral patterns were analysed for patients with active AD in 2019. The overall prevalence of AD was stable at 2.4% per year during the period 2015-2019. In 2019, mean patient age (± standard deviation) was 52.6 ± 21.0 years, 58.2% of patients were female and mean disease duration was 9.4 ± 5.9 years. The most prescribed treatment was topical corticosteroids, in 78.5% of patients. 36.7% of patients with moderate-to-severe AD were prescribed systemic agents and 59.8% (vs. 32.3% of patients with mild AD) were referred to any secondary care or specialist treatment. The prevalence of active AD in the adult UK population was stable over the 5-year period (2015-2019) and was comparable to estimates from similar studies based on UK primary healthcare records.

The impact of environmental enrichment on the murine inflammatory immune response.

Living in a mentally and physically stimulating environment has been suggested to have a beneficial effect on the immune response. This study investigates these effects, utilizing a 2-week program of environmental enrichment (EE) and 2 models of acute inflammation: zymosan-induced peritonitis (ZIP) and the cecal ligation and puncture (CLP) model of sepsis. Our results revealed that following exposure to EE, mice possessed a significantly higher circulating neutrophil to lymphocyte ratio compared with control animals. When subject to ZIP, EE animals exhibit enhanced neutrophil and macrophage influx into their peritoneal cavity. Corresponding results were found in CLP, where we observed an improved capacity for enriched animals to clear systemic microbial infection. Ex vivo investigation of leukocyte activity also revealed that macrophages from EE mice presented an enhanced phagocytic capacity. Supporting these findings, microarray analysis of EE animals revealed the increased expression of immunomodulatory genes associated with a heightened and immunoprotective status. Taken together, these results provide potentially novel mechanisms by which EE influences the development and dynamics of the immune response.

Galectin-3: A Positive Regulator of Leukocyte Recruitment in the Inflamed Microcirculation.

In vivo and ex vivo imaging were used to investigate the function of galectin-3 (Gal-3) during the process of leukocyte recruitment to the inflamed microcirculation. The cremasteric microcirculation of wild-type (C57BL/6), Gal-3-/-, and CX3CR1gfp/+ mice were assessed by intravital microscopy after PBS, IL-1ß, TNF-α, or recombinant Gal-3 treatment. These cellular responses were investigated further using flow-chamber assays, confocal microscopy, flow cytometry, PCR analysis, and proteome array. We show that mechanisms mediating leukocyte slow rolling and emigration are impaired in Gal-3-/- mice, which could be because of impaired expression of cell adhesion molecules and an altered cell surface glycoproteome. Local (intrascrotal) administration of recombinant Gal-3 to wild-type mice resulted in a dose-dependent reduction in rolling velocity associated with increased numbers of adherent and emigrated leukocytes, ∼50% of which were Ly6G+ neutrophils. Intrascrotal administration of Gal-3 to CX3CR1gfp/+ mice confirmed that approximately equal numbers of monocytes are also recruited in response to this lectin. Exogenous Gal-3 treatment was accompanied by increased proinflammatory cytokines and chemokines within the local tissue. In conclusion, this study unveils novel biology for both exogenous and endogenous Gal-3 in promoting leukocyte recruitment during acute inflammation.

Methods for assessing the effects of galectins on leukocyte trafficking.

Numerous protocols exist for investigating leukocyte recruitment both in vitro and in vivo. Here we describe three of these methods; an in vitro flow chamber assay, intravital microscopy, and zymosan-induced peritonitis, and give details as to how they can be used to study the actions of galectins on this crucial process.

Endogenous galectin-1 exerts tonic inhibition on experimental arthritis.

Little is known about the role(s) of endogenous galectin-1 (Gal-1) in arthritis. In this study we queried whether antiarthritic functions for this effector of endogenous anti-inflammation could be unveiled by studying collagen-induced arthritis in Gal-1(-/-) mice. Gal-1(-/-) and C57BL/6J [wild-type (WT)] mice received an immunization of chicken type II collagen (CII) in CFA followed by a booster on day 21, which consisted of CII in IFA. Animals were monitored for signs of arthritis from day 14 onward. Clinical and histological signs of arthritis were recorded, and humoral and cellular immune responses against CII were analyzed. A distinct disease penetrance was apparent, with ~ 70% of Gal-1(-/-) mice developing arthritis compared with ~ 50% in WT animals. Gal-1(-/-) mice also exhibited an accelerated disease onset and more severe arthritis characterized by significantly elevated clinical scores. Postmortem analyses (day 42) revealed higher levels of IgG1 and IgG2b anti-CII Ig isotypes in the serum of Gal-1 null animals compared with WT. Finally, T cell responses following ex vivo stimulation with CII revealed a greater degree of proliferation in T cells of Gal-1(-/-) mice compared with WT, which was associated with increased production of IL-17 and IL-22. These data suggest the novel idea that endogenous Gal-1 is an inhibitory factor in the development of arthritis affecting disease severity. We have also highlighted the importance of endogenous Gal-1 in regulating T cell reactivity during experimental arthritis.

Loss of substance P and inflammation precede delayed neurodegeneration in the substantia nigra after cerebral ischemia.

Focal cerebral ischemia leads to delayed neurodegeneration in remote brain regions. The substantia nigra (SN) does not normally show primary neuronal death after ischemic events affecting the striatum, but can exhibit delayed neuronal loss after the ischemic injury through mechanisms that are unknown. No data are available in mice showing acute post-stroke inflammation and remote injury in the SN. Substance P (SP), a mediator of neurogenic inflammation, is a key element of the striato-nigral circuitry, but alterations of SP in the SN have not been studied after acute striatal injury. Inflammation, a key contributor to neuronal death, is found in the SN after striatal ischemia, but it is unknown whether it precedes or occurs concomitantly with neuronal death. We hypothesised that focal striatal ischemia induces changes in SP levels in the SN and that inflammation precedes neuronal death in the SN. Using the middle cerebral artery occlusion model, we found a significant loss of SP in the ipsilateral SN 24h after striatal ischemia in mice. In the same area where SP loss occurs, significant glial and vascular activation, but no neuronal death, were observed. In contrast, a marked neuronal loss was observed within six days in the area of SP loss and inflammation. Our data suggest that focal loss of SP and early inflammatory changes in the SN precede remote neuronal injury after striatal ischemic damage. These observations may have important implications for motor impairment in stroke patients and indicate that striatal ischemia might facilitate Parkinson's disease development.

The effect of galectins on leukocyte trafficking in inflammation: sweet or sour?

The trafficking of leukocytes from the blood stream to the surrounding tissue is a fundamental feature of an inflammatory response. Although many of the adhesion molecules and chemokines that direct leukocyte trafficking have been identified, there is still much to be discovered, particularly with regard to the persistence of leukocyte infiltrates in chronic inflammation. Elucidating the molecular mechanisms involved in this process is critical to understanding and treating inflammatory pathologies. Recent studies have identified members of the galectin family as immunoregulatory proteins. Included among the actions of galectins are modulatory effects, both positive and negative, on leukocyte recruitment. The focus of this review is to summarize current knowledge on the role of galectins in leukocyte trafficking during inflammation. A better understanding of the function of this family of endogenous lectins will open new avenues for innovative drug discovery.