Significance We identified a previously undescribed disease mechanism for psoriasis (Ps) and psoriasis arthritis (PsA)-like disease by developing a new mouse model having characteristic features similar to those of Ps and PsA in human patients. Mannan-induced activation of tissue macrophages triggers IL-17A secretion from γδ T cells, causing Ps-like inflammation. Such inflammation was significantly increased under a reduced oxidative environment. Increased frequency of monocytes/macrophages, depletion experiments, and the disease suppressor function of macrophage-derived reactive oxygen species clearly argue in favor of a role for monocytes/macrophages in this disease model, which is in accordance with the findings in patients with the psoriatic form of skin lesions and arthritis. This novel PsA model could be immensely useful to test new therapeutics for patients with Ps and PsA.

Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody-induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcRγ chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcRγ chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcRγ chain-deficient mice or mice lacking activating FcγRs in neurons. In summary, this study defines functional coupling between autoantibodies and pain transmission that may facilitate the development of new disease-relevant pain therapeutics.

Human skin microbiota might play an important role in maintaining skin health and potentially prevent premature skin ageing. The use of probiotics in therapeutic skin applications is an attractive idea, as it could offer an alternative option for certain inflammatory skin disorders and dry or sensitive skin. Here, we investigated for the first time, a comparative study of live and the lysate products of probiotic strain Lactobacillus reuteri DSM 17938 in skin topical applications using ex vivo skin models focusing on anti‐inflammatory and skin barrier function and in vitro assays for antimicrobial activity. Our results in ultraviolet B radiation (UVB‐R)‐induced inflammation model demonstrated that both live bacteria and the lysate of L. reuteri DSM 17938 reduced proinflammatory IL‐6 and IL‐8, illustrated in both reconstructed human epidermis (RHE) and native skin models. Live L reuteri DSM 17938 significantly increased aquaporin 3 (AQP3) gene expression, while the lysate enhanced laminin A/B levels in a healthy (unstimulated) state of RHE, suggesting a positive impact on skin barrier. In addition, live L. reuteri DSM 17938 had antimicrobial action against pathogenic skin bacteria (Staphylococcus aureus, Streptococcus pyogenes M1, Cutibacterium acnes AS12, Pseudomonas aeruginosa), whereas the lysate did not have such an effect. Therefore, it is hypothesized that L. reuteri DSM 17938 could be beneficial for general skin health, to avoid the UVB‐R‐mediated inflammatory cascade and/or prevent photoageing, improve barrier function or in the management of unhealthy skin prone to inflammatory conditions due to its antimicrobial, anti‐inflammatory and skin barrier enhancing functions.

Higher demands on skin care cosmetic products for strong performance drive intense research to understand the mechanisms of skin aging and design strategies to improve overall skin health. Today we know that our needs and influencers of skin health and skin aging change throughout our life journey due to both extrinsic factors, such as environmental factors and lifestyle factors, as well as our intrinsic factors. Furthermore, we need to consider our microflora, a collection of micro-organisms such as bacteria, viruses, and fungi, which is a living ecosystem in our gut and on our skin, that can have a major impact on our health. Here, we are viewing a holistic approach to understand the collective effect of the key influencers of skin health and skin aging both reviewing how each of them impact the skin, but more importantly to identify molecular conjunction pathways of these different factors in order to get a better understanding of the integrated “genome-microbiome-exposome” effect. For this purpose and in order to translate molecularly the impact of the key influencers of skin health and skin aging, we built a digital model based on system biology using different bioinformatics tools. This model is considering both the positive and negative impact of our genome (genes, age/gender), exposome: external (sun, pollution, climate) and lifestyle factors (sleep, stress, exercise, nutrition, skin care routine), as well as the role of our skin microbiome, and allowed us in a first application to evaluate the effect of the genome in the synthesis of collagen in the skin and the determination of a suitable target for boosting pro-collagen synthesis. In conclusion, we have, through our digital holistic approach, defined the skin interactome concept, as an advanced tool to better understand the molecular genesis of skin aging and further develop a strategy to balance the influence of the exposome and microbiome to protect, prevent, and delay the appearance of skin aging signs and preserve good skin health condition. In addition, this model will aid in identifying and optimizing skin treatment options based on external triggers, as well as helping to design optimal treatments modulating the intrinsic pathways.

We have addressed the importance of B cell tolerance to collagen type II, a matrix protein, which is a target in rheumatoid arthritis (RA) and its mouse models. We generated a germline-encoded anti-collagen type II (CII) IgH replacement anti-C1 B cell mouse strain (ACB) to investigate how B cell tolerance to CII, a matrix protein, is subverted and to further understand pathogenesis of RA. Phenotypic analysis revealed that CII-specific B cells were surprisingly neither deleted nor anergized. Instead, they were readily detected in all lymphoid organs. Spontaneously produced autoantibodies could bind directly to cartilage surface without detectable pathology. However, exaggerated arthritis was seen after injection of anti-CII Abs specific for other epitopes. In addition, Abs from CII-specific hybridomas generated from ACB mice induced arthritis. Interestingly, IgH/L chain sequence data in B cell hybridomas revealed a lack of somatic mutations in autoreactive B cells. The ACB model provides the first possibility, to our knowledge, to study B cell tolerance to a matrix protein, and the observations made in the study could not be predicted from previous models. B cell-reactive epitopes on CII are largely shared between human RA and rodent CII-induced arthritis; this study, therefore, has important implications for further understanding of pathological processes in autoimmune diseases like RA.