Explore the vast range of titles available.

The p38 mitogen-activated protein kinase (p38-MAPK) is a crucial signaling pathway closely involved in several physiological and cellular functions, including cell cycle, apoptosis, gene expression, and responses to stress stimuli. It also plays a central role in inflammation and immunity. Owing to disparate p38-MAPK functions, it has thus far formed an elusive drug target with failed clinical trials in inflammatory diseases due to challenges including hepatotoxicity, cardiac toxicity, lack of efficacy, and tachyphylaxis, which is a brief initial improvement with rapid disease rebound. To overcome these limitations, downstream antagonism of the p38 pathway with a MAPK-activated protein kinase (MAPKAPK, also known as MK2) blockade has demonstrated the potential to abrogate inflammation without the prior recognized toxicities. Such MK2 inhibition (MK2i) is associated with robust suppression of key pro-inflammatory cytokines, including TNFα and IL-6 and others in experimental systems and in vitro. Considering this recent evidence regarding MK2i in inflammatory arthritis, we revisit the p38-MAPK pathway and discuss the literature encompassing the challenges of p38 inhibitors with a focus on this pathway. We then highlight how novel MK2i strategies, although encouraging in the pre-clinical arena, may either show evidence for efficacy or the lack of efficacy in emergent human trials data from different disease settings.

The skin barrier would not function without IL-1 family members, but their physiological role in the immunological aspects of skin barrier function are often overlooked. This review summarises the role of IL-1 family cytokines (IL-1α, IL-1β, IL-1Ra, IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-36Ra, IL-37 and IL-38) in the skin. We focus on novel aspects of their interaction with commensals and pathogens, the important impact of proteases on cytokine activity, on healing responses and inflammation limiting mechanisms. We discuss IL-1 family cytokines in the context of IL-4/IL-13 and IL-23/IL-17 axis-driven diseases and highlight consequences of human loss/gain of function mutations in activating or inhibitory pathway molecules. This review highlights recent findings that emphasize the importance of IL-1 family cytokines in both physiological and pathological cutaneous inflammation and emergent translational therapeutics that are helping further elucidate these cytokines.

Historically inflammation against self was considered autoimmune which stems back to the seminal observations by Ehrlich who described serum factors, now known to be autoantibodies produced by B lineage cells that mediate “horror autotoxicus”. The 20 th century elucidation of B- and T-cell adaptive immune responses cemented the understanding of the key role of adaptive immune responses in mediating pathology against self. However, Mechnikov shared the Nobel Prize for the discovery of phagocytosis, the most rudimentary aspect of innate immunity. Fast forward some 100 years and an immunogenetic understanding of innate immunity led to the categorising of innate immunopathology under the umbrella term ‘auto inflammation’ and terminology such as “horror autoinflammaticus” to highlight the schism from the classical adaptive immune understanding of autoimmunity. These concepts lead to calls for a two-tiered classification of inflammation against self, but just as innate and adaptive immunity are functionally integrated, so is immunopathology in many settings and the concept of an autoimmune to autoinflammation continuum emerged with overlaps between both. Herein we describe several historically designated disorders of adaptive immunity where innate immunity is key, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) where the immunopathology phenotype is strongly linked to major histocompatibility complex (MHC) class II associations and responds to drugs that target T-cells. We also consider MHC-I-opathies including psoriasis and Behcet's disease(BD) that are increasingly viewed as archetype CD8 T-cell related disorders. We also briefly review the key role of barrier dysfunction in eczema and ulcerative colitis (UC) where innate tissue permeability barrier dysfunction and microbial dysbiosis contributes to prominent adaptive immune pathological mechanisms. We also highlight the emerging roles of intermediate populations of lymphocytes including gamma delta (γδ) and mucosal-associated invariant T (MAIT) cells that represent a blend of adaptive immune plasticity and innate immune rapid responders that may also determine site specific patterns of inflammation.

The interleukin-36 receptor antagonist (IL-36Ra) which regulates IL-36α, -β and -γ is linked to psoriatic inflammation, especially loss-of-function mutations in pustular psoriasis subtypes. As observed with other IL-1 superfamily proteins, the IL-36 members require N-terminal cleavage for full biological activity but the mechanisms of IL-36Ra activation remain poorly defined. Using different blood leukocyte and skin resident cell preparations and recombinant proteins, we have identified that neutrophil elastase, but not other neutrophil derived proteases, cleaves IL-36Ra into its highly active antagonistic form. The activity of this processed form of IL-36Ra was confirmed in human primary dermal fibroblasts and keratinocytes and in skin equivalents. A significant dose dependent reduction of IL-36γ induced IL-8 and chemokine ligand 20 (CCL20) levels were detected following addition of the cleaved IL-36Ra compared to full length IL-36Ra. By activating IL-36Ra, the neutrophil derived protease can inhibit IL-36 induced chemokine production, including IL-8 and CCL20 and reduce further inflammatory cell infiltration. These findings strongly indicate neutrophil elastase to be a key enzyme in the biological function of IL-36Ra and that neutrophils can play a regulatory role in psoriatic inflammation with regard to balancing the pro-inflammatory activity of IL-36.

The IL-1 family member cytokine IL-36γ is recognised as key mediator in the immunopathology of psoriasis, hallmarks of which involve the activation of both resident and infiltrating inflammatory myeloid cells and aberrant angiogenesis. This research demonstrates a role for IL-36γ in both myeloid activation and angiogenesis. We show that IL-36γ induces the production of psoriasis-associated cytokines from macrophages (IL-23 and TNFα) and that this response is enhanced in macrophages from psoriasis patients. This effect is specific for IL-36γ and could not be mimicked by other IL-1 family cytokines such as IL-1α. IL-36γ was also demonstrated to induce endothelial tube formation and branching, in a VEGF-A-dependent manner. Furthermore, IL-36γ-stimulated macrophages potently activated endothelial cells and led to increased adherence of monocytes, effects that were markedly more pronounced for psoriatic macrophages. Interestingly, regardless of stimulus, psoriasis monocytes showed increased adherence to both the stimulated and unstimulated endothelium when compared with monocytes from healthy individuals. Collectively, these findings show that IL-36γ has the potential to enhance endothelium directed leucocyte infiltration into the skin and strengthen the IL-23/IL-17 pathway adding to the growing evidence of pathogenetic roles for IL-36γ in psoriatic responses. Our findings also point to a cellular response, which could potentially explain cardiovascular comorbidities in psoriasis in the form of endothelial activation and increased monocyte adherence.

Although IL-17F is important in psoriasis, the rudimentary biology of IL-17F in the human enthesis remains undefined. We aimed to characterise IL-23-dependent and independent IL-17F production from entheseal innate and adaptive T cells and determine the impact of IL-17F on entheseal stromal function and mesenchymal stem cell (MSC) osteogenesis. Anti-CD3 and anti-CD28 activated human spinal entheseal T cells were immunophenotyped using multi-parameter flow cytometry and a 36-marker Cytometry by Time-Of-Flight (CyTOF) with cytokine profiling, including IL-17A, IL-17F, and TNF (n = 10). IL-17A, IL-17F, and TNF stimulation of entheseal MSC stromal function was evaluated using RNA-seq and by measuring CCL20 protein expression following stimulation with TNF in combination with IL-17A or IL-17F. The osteogenic effects of IL-17A and IL-17F on MSC differentiation were assessed. Inducible IL-17A and IL-17F expression was predominantly from CD4 T cells and CD4+CD25+ T cells, with higher levels of IL-17F at 72 hr. IL-23 significantly increased IL-17F (p ≤ 0.0001) but not IL-17A. Either IL-17A or IL-17F in combination with TNF dramatically upregulated CCL20 protein expression and substantially changed entheseal stromal transcriptome, with differences in gene expression and pathway activation seen between IL-17A or IL-17F stimulation. However, entheseal MSC osteogenesis was not significantly changed. There was differential induction of IL-17A and IL-17F from innate and adaptive entheseal T cells, with further significant IL-17F augmentation by IL-23, but not IL-17A. Furthermore, the synergistic effects of IL-17A or IL-17F and TNF on stromal function provide the basis for further enthesis IL-17F biology interrogation.

RNA aptamers are synthetic single stranded RNA oligonucleotides that function analogously to antibodies. Recently, they have shown promise for use in treating inflammatory skin disease as, unlike antibody-based biologics, they are able to enter the skin following topical administration. However, it is important to understand the inflammatory milieu into which aptamers are delivered, as numerous immune-modulating mediators will be present at abnormal levels. LL-37 is an important immune-modifying protein upregulated in several inflammatory skin conditions, including psoriasis, rosacea and eczema. This inflammatory antimicrobial peptide is known to complex nucleic acids and induce both inflammatory and interferon responses from keratinocytes. Given the attractive notion of using RNA aptamers in topical medication and the prevalence of LL-37 in these inflammatory skin conditions, we examined the effect of LL-37 on the efficacy and safety of the anti-IL-17A RNA aptamer, Apt 21-2. LL-37 was demonstrated to complex with the RNA aptamer by electrophoretic mobility shift and filter binding assays. In contrast to free Apt 21-2, LL-37-complexed Apt 21-2 was observed to efficiently enter both keratinocytes and fibroblasts by confocal microscopy. Despite internalization of LL-37-complexed aptamers, measurement of inflammatory mediators and interferon stimulated genes showed LL-37-complexed Apt 21-2 remained immunologically inert in keratinocytes, fibroblasts, and peripheral blood mononuclear cells including infiltrating dendritic cells and monocytes. The findings of this study suggest RNA aptamers delivered into an inflammatory milieu rich in LL-37 may become complexed and subsequently internalized by surrounding cells in the skin. Whilst the results of this study indicate delivery of RNA aptamers into tissue rich in LL-37 should not cause an unwarranted inflammatory of interferon response, these results have significant implications for the efficacy of aptamers with regards to extracellular vs. intracellular targets that should be taken into consideration when developing treatment strategies utilizing RNA aptamers in inflamed tissue.

ObjectiveObesity and age are strongly linked to severe COVID-19 pneumonia where immunomodulatory agents including Janus kinase inhibitors have shown benefits but the efficacy of such therapy in viral pneumonia is not well understood. We evaluated the impact of obesity and age on survival following baricitinib therapy for severe COVID-19.MethodsA post hoc analysis of the COV-BARRIER multicentre double-blind randomised study of baricitinib versus placebo (PBO) with an assessment of 28-day mortality was performed. All-cause mortality by day 28 was evaluated in a Cox regression analysis (adjusted to age) in three different groups according to body mass index (BMI) (<25 kg/m2, 25–30 kg/m2 and >30 kg/m2) and age <65 years and ≥65 years.ResultsIn the high BMI group (>25 kg/m2), baricitinib therapy showed a significant survival advantage compared with PBO (incidence rate ratio (IRR) for mortality by day 28 0.53 (95% CI 0.32 to 0.87)) and 0.66 (95% CI 0.46 to 0.94) for the respective <65 years and ≥65 years, respectively. The 28-day all-cause-mortality rates for BMI over 30 were 5.62% for baricitinib and 9.22% for PBO (HR=0.6, p<0.05). For BMI under 25 kg/m2, irrespective of age, baricitinib therapy conferred no survival advantage (IRR of 1.89 (95% CI 0.49 to 7.28) and 0.95 (95% CI 0.46 to 1.99) for <65 years and ≥65 years, respectively) ((mortality 6.6% baricitinib vs 8.1 in PBO), p>0.05).ConclusionThe efficacy of baricitinib in COVID-19 pneumonia is linked to obesity suggesting that immunomodulatory therapy benefit is associated with obesity-associated inflammation.

ObjectiveThe increasing use of biological therapies has led to the paradoxical finding that monoclonal antibody therapy for one inflammatory disease can sometimes induce another inflammatory disease. Recently, the use of anti-IL-5 (IL, interleukin) antibody therapies for severe asthma has been associated with the onset of rheumatoid arthritis (RA) and other inflammatory rheumatological disease. We undertook this audit to identify the prevalence of this finding across a large clinical cohort of patients receiving anti-IL-5 therapy.MethodsAll patients currently receiving mepolizumab or benralizumab for severe asthma across the Leeds Teaching Hospitals NHS Trust’s (LTHT) Respiratory Service were included. Electronic records for each patient were searched to identify clinical and biochemical manifestations of inflammatory rheumatological disease following the initiation of anti-IL-5 therapy.Results142 patients, with a mean duration of 3.5 years on therapy, were included (89 mepolizumab, 53 benralizumab). 17 patients developed new arthralgias (nine mepolizumab, eight benralizumab), however only one of these patients (on mepolizumab) had raised acute phase reactants and newly positive anti-CCP antibody (ACPA) and rheumatoid factor and was the only patient to receive a formal diagnosis of RA.ConclusionAlthough ACPA positive RA has now been reported in a handful of case reports, we noted a very low rate of evolution into RA or inflammatory arthritis, at least in the short-medium term under anti-IL-5 therapy. This challenges the emerging suggestion that anti-IL-5 biologics may be triggering RA.

Since the original description of spondyloarthritis 50 years ago, results have demonstrated similarities and differences between ankylosing spondylitis (AS) and axial psoriatic arthritis (PsA). HLA-B27 gene carriage in axial inflammation is linked to peri-fibrocartilaginous sacroiliac joint osteitis, as well as to spinal peri-entheseal osteitis, which is often extensive and which provides a crucial anatomical and immunological differentiation between the AS and PsA phenotypes. Specifically, HLA-B27-related diffuse bone marrow oedema (histologically an osteitis) and bone marrow fatty corners detected via magnetic resonance imaging, as well as radiographic changes such as sacroiliitis, vertebral squaring, corner erosions and Romanus lesions, all indicate initial bone phenotypes in HLA-B27+ axial disease. However, in much of PsA with axial involvement, enthesitis primarily manifests in ligamentous soft tissue as ‘ligamentitis’, with characteristic lesions that include para-syndesmophytes and sacroiliac joint bony sparing. Like axial PsA, diffuse idiopathic skeletal hyperostosis phenotypes, which can be indistinguishable from PsA, exhibit a thoracic and cervical spinal ligamentous soft-tissue tropism, clinically manifesting as syndesmophytosis that is soft-tissue-centric, including paravertebral soft-tissue ossification and sacroiliac soft-ligamentous ossification instead of joint-cavity fusion. The enthesis bone and soft tissues have radically different immune cell and stromal compositions, which probably underpins differential responses to immunomodulatory therapy, especially IL-23 inhibition.In this Perspective, the authors propose that despite the known similarities between ankylosing spondylitis and axial psoriatic arthritis, the localization of inflammation to bone in ankylosing spondylitis and to ligamentous soft tissue in axial axial psoriatic arthritis differentiates these diseases and has important implications for diagnosis, pathology and treatment.