bims-adipim 2023-06-11 papers

Issue of 2023–06–11
six papers selected by
Matthew C. Sinton, University of Glasgow

Diabetes Obes Metab. 2023 Jun 05.

The role of adiponectin for immune cell function in metabolic diseases.

Adiponectin, as an indispensable regulator of the immune system, is the most abundant adipokine and is mainly produced by white adipose tissue. Adiponectin mediates the positive effects on systemic metabolism by regulating associated downstream signalling pathways; however, accumulating evidence shows that adiponectin plays an important role in regulating the function of innate and adaptive immune cells in the development of obesity and its related diseases. In this review, we focus on the biological function of adiponectin in regulating innate and adaptive immunity and outline the key role of adiponectin in various metabolic diseases, which will highlight a potential direction for adiponectin-based therapeutic interventions for metabolic diseases.

Keywords: adaptive immunity; adiponectin; inflammation; innate immunity; metabolic diseases

DOI: https://doi.org/10.1111/dom.15151

Nat Aging. 2023 Jun 08.

Targeting lymphoid-derived IL-17 signaling to delay skin aging.

Paloma Solá, Elisabetta Mereu, Júlia Bonjoch, Marta Casado-Peláez, Neus Prats, Mònica Aguilera, Oscar Reina, Enrique Blanco, Manel Esteller, Luciano Di Croce, Holger Heyn, Guiomar Solanas, Salvador Aznar Benitah.

Skin aging is characterized by structural and functional changes that contribute to age-associated frailty. This probably depends on synergy between alterations in the local niche and stem cell-intrinsic changes, underscored by proinflammatory microenvironments that drive pleotropic changes. The nature of these age-associated inflammatory cues, or how they affect tissue aging, is unknown. Based on single-cell RNA sequencing of the dermal compartment of mouse skin, we show a skew towards an IL-17-expressing phenotype of T helper cells, γδ T cells and innate lymphoid cells in aged skin. Importantly, in vivo blockade of IL-17 signaling during aging reduces the proinflammatory state of the skin, delaying the appearance of age-related traits. Mechanistically, aberrant IL-17 signals through NF-κB in epidermal cells to impair homeostatic functions while promoting an inflammatory state. Our results indicate that aged skin shows signs of chronic inflammation and that increased IL-17 signaling could be targeted to prevent age-associated skin ailments.

DOI: https://doi.org/10.1038/s43587-023-00431-z

bioRxiv. 2023 May 18. pii: 2023.05.16.540975. [Epub ahead of print]

Adipocytes regulate fibroblast function, and their loss contributes to fibroblast dysfunction in inflammatory diseases.

Accelerating Medicines Partnership Program: Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network

Fibroblasts play critical roles in tissue homeostasis, but in pathologic states can drive fibrosis, inflammation, and tissue destruction. In the joint synovium, fibroblasts provide homeostatic maintenance and lubrication. Little is known about what regulates the homeostatic functions of fibroblasts in healthy conditions. We performed RNA sequencing of healthy human synovial tissue and identified a fibroblast gene expression program characterized by enhanced fatty acid metabolism and lipid transport. We found that fat-conditioned media reproduces key aspects of the lipid-related gene signature in cultured fibroblasts. Fractionation and mass spectrometry identified cortisol in driving the healthy fibroblast phenotype, confirmed using glucocorticoid receptor gene ( NR3C1 ) deleted cells. Depletion of synovial adipocytes in mice resulted in loss of the healthy fibroblast phenotype and revealed adipocytes as a major contributor to active cortisol generation via Hsd11 β 1 expression. Cortisol signaling in fibroblasts mitigated matrix remodeling induced by TNFα- and TGFβ, while stimulation with these cytokines repressed cortisol signaling and adipogenesis. Together, these findings demonstrate the importance of adipocytes and cortisol signaling in driving the healthy synovial fibroblast state that is lost in disease.

DOI: https://doi.org/10.1101/2023.05.16.540975

J Diabetes Investig. 2023 Jun 08.

Weight loss improves inflammation by T helper 17 cells in an obese patient with psoriasis at high risk for cardiovascular events.

Yoshiro Maezawa, Yusuke Endo, Satomi Kono, Tomohiro Ohno, Yuumi Nakamura, Naoya Teramoto, Ayano Yamaguchi, Kazuto Aono, Takuya Minamizuka, Hisaya Kato, Takahiro Ishikawa, Masaya Koshizaka, Minoru Takemoto, Toshinori Nakayama, Koutaro Yokote.

Psoriasis is a chronic inflammatory skin disease that is associated with obesity and myocardial infarction. Obesity-induced changes in lipid metabolism promote T helper 17 (Th17) cell differentiation, which in turn promotes chronic inflammation. Th17 cells have central roles in many inflammatory diseases, including psoriasis and atherosclerosis; however, whether treatment of obesity attenuates Th17 cells and chronic inflammatory diseases has been unknown. In this study, we found an increase in Th17 cells in a patient with obesity, type 2 diabetes and psoriasis. Furthermore, weight loss with diet and exercise resulted in a decrease in Th17 cells and improvement of psoriasis. This case supports the hypothesis that obesity leads to an increase in Th17 cells and chronic inflammation of the skin and blood vessel walls, thereby promoting psoriasis and atherosclerosis.

Keywords: Atherosclerosis; Psoriasis; Th17

DOI: https://doi.org/10.1111/jdi.14037

J Allergy Clin Immunol. 2023 Jun 02. pii: S0091-6749(23)00705-4. [Epub ahead of print]

Single-cell transcriptomics suggest distinct upstream drivers of IL-17A/F in hidradenitis versus psoriasis.

Jaehwan Kim, Jongmi Lee, Xuan Li, Hyun Soo Lee, Katherine Kim, Vasuma Chaparala, William Murphy, Wei Zhou, Junyue Cao, Michelle A Lowes, James G Krueger.

BACKGROUND: Based on the mounting evidence that Type 17 T-cells (T17 cells) and increased IL-17 play a key role in driving hidradenitis suppurativa (HS) lesion development, biologics used previously in psoriasis that block signaling of IL-17A and/or IL-17F isoforms have been repurposed to treat HS.
OBJECTIVE: Our research aimed to characterize the transcriptome of HS T17 cells compared to the transcriptome of psoriasis T17 cells, along with their ligand-receptor interactions with neighborhood immune cell subsets.
METHODS: Single-cell data of 12,300 cutaneous immune cells from 8 de-roofing surgical HS skin samples including dermal tunnels were compared with single-cell data of psoriasis skin (19,525 cells from 11 samples) and control skin (11,920 cells from 10 samples). All of the single-cell data were generated by the same protocol.
RESULTS: HS T17 cells expressed lower levels of IL23R and higher levels of IL1R1 and IL17F compared to psoriasis T17 cells (p < 0.05). HS regulatory T-cells (Tregs) expressed higher levels of IL1R1 and IL17F compared to psoriasis Tregs (p < 0.05). Semimature dendritic cells (DCs) were the major immune cell subsets expressing IL1B in HS, and IL-1B ligand-receptor interactions between semimature DCs and T17 cells were increased in HS compared to psoriasis (p < 0.05). HS dermal tunnel keratinocytes (KCs) expressed inflammatory cytokines (IL17C, IL1A, IL1B, and IL6) which differed from the HS epidermis KCs (IL36G) (p < 0.05). IL6, which synergizes with IL1B to maintain cytokine expression in T17 cells, was mainly expressed by fibroblasts in HS, which also expressed IL11+ inflammatory fibroblast genes (IL11, IL24, IL6, and POSTN) involved in paracrine IL-1/IL-6 loop.
CONCLUSION: The IL-1B-T17 cell cytokine axis is likely a dominant pathway in HS with HS T17 cells activated by IL-1B signaling, unlike psoriasis T17 cells which are activated by IL-23 signaling.
CLINICAL IMPLICATION: Biologics targeting IL-17 isoforms and IL-1B may be effective for HS but biologics targeting IL-23 may be less effective for HS.

Keywords: Hidradenitis suppurativa; IL-1; IL-17A; IL-17F; IL-1R1; IL-23; T-cell; dendritic cell; fibroblast; keratinocyte; psoriasis; single-cell RNA sequencing; type 17 T-cells

DOI: https://doi.org/10.1016/j.jaci.2023.05.012

Curr Stem Cell Res Ther. 2023 Jun 05.

Mechanically Activated Adipose Tissue as a Source for Novel Therapies in Neurological Disease/Injury.

Alfredo Gorio, Hongkun Gao, Marco Klinger, Valeriano Vinci, Francesca Paino.

In this review, we describe a new avenue that involves the therapeutic use of human adipose tissue. In the past two decades, thousands of papers have described the potential clinical use of human fat and adipose tissue. Moreover, mesenchymal stem cells have been a source of great enthusiasm in clinical studies, and these have generated curiosity at academic levels. On the other hand, they have created considerable commercial business opportunities. High expectations have emerged for curing some recalcitrant diseases or reconstructing anatomically defective human body parts, but several concerns have been raised by generating criticism on the clinical practice that have not been substantiated by rigorous scientific evidence. However, in general, the consensus is that human adipose-derived mesenchymal stem cells inhibit the production of inflammatory cytokines and stimulate the production of anti-inflammatory cytokines. Here, we show that the application of a mechanical elliptical force for several minutes to human abdominal fat activates anti-inflammatory properties and gene-related expression. This may pave the way for new unexpected clinical developments.

Keywords: Spinal cord injury; adipose tissue; cell therapies; inflammation; mechanical activation; neurogenesis.; neuroprotection

DOI: https://doi.org/10.2174/1574888X18666230605120546