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Local IL-17 orchestrates skin aging

Paloma Solá, Elisabetta Mereu, Júlia Bonjoch, Marta Casado, Oscar Reina, Enrique Blanco, Manel Esteller, Luciano DiCroce, Holger Heyn, Guiomar Solanas , Salvador Aznar-Benitah

Posted on: 2 March 2022

Preprint posted on 31 January 2022

Interleukin 17 is behind wrinkles and loss of hair

Selected by Andrea Irazoki

Categories: cell biology, immunology, physiology

BACKGROUND

Skin aging is a biological process characterized by architectural and functional alterations that promote reduced wound healing capacity and compromised protective role against external pathogens [1]. Many different types of cells compose the skin niche (Figure 1), which confers this tissue with a number of functions, including maintaining body temperature, gathering sensory information from the environment and as a protective barrier [2].

Figure 1: The human skin niche and the residing cell types. Dermis and epidermis are two of the main skin layers. On one hand, the dermis contains different immune cell types, as well as fibroblasts and endothelial cells. On the other hand, the epidermis contains melanocytes, keratinocytes at different differentiation states and Langerhans cells, a unique population of tissue-residing macrophages. From Nestle FO., et al., 2009.

 

Given the high complexity of the skin architecture, synergic malfunctioning of the different cell populations results in its age-associated frailty. Furthermore, chronic inflammation has been widely demonstrated to modulate a diversity of processes underlying aging in different tissues [3], including the skin. Nonetheless, there is lack of evidence on the types of skin immune cells responsible for the pro-inflammatory environment associated to aging, and on the identity of the inflammatory cytokines that play a role.

To address this knowledge gap and using transcriptomics at the single-cell level, Paloma Solá and colleagues decipher the major transcriptional changes of different cell populations residing in the skin that take place during aging and they identify one of the key players driving skin aging.

 

KEY FINDINGS

In this study, the authors performed single-cell RNA-sequencing (scRNA-seq) of the different skin cell populations from adult and aged mice (17 to 25-, and 80 to 90-weeks of age, respectively). For this, the authors combined dermis or epidermis cell isolation and sorting, with RNA extraction and sequencing. It is worth noting that this process was performed in the dark period, to coincide with the active phases of mice.

By using this approach, transcription profiles linked to defective functions and increased inflammation were observed in both non-immune and immune dermal cells of aged mice. Among the former, Schwann cells appeared to be less efficient in their regenerative functions in skin, whereas endothelial cells and fibroblasts showed a shift towards a more pro-inflammatory state. Among the latter, dermal myeloid cells, T cells and innate lymphoid cells (ILCs) presented a remarkable upregulation of genes involved in different pro-inflammatory signaling pathways. Importantly, the authors noticed that in the case of specific T cell subsets and ILCs, these genes were predominantly related to the pro-inflammatory cytokine interleukin 17 (IL-17).

To address the physiological contribution of IL-17 signaling to skin aging, the authors treated aged mice (73-weeks-old) with IL-17 neutralizing antibodies for 12 weeks. They then assessed the transcriptomics of skin cells at single-cell level, as well as physiological parameters, such as the thickness of the cornified layer and the whole epidermal layer, as well as hair growth. First, the authors observed that IL-17 neutralization ameliorated the pro-inflammatory transcriptional state of dermal cells. Strikingly, the predominant anti-inflammatory effects were observed in non-immune dermal cells (fibroblasts, endothelial cells and Schwann cells). This is an interesting observation, since it suggests that non-immune dermal cells are most sensitive to anti-inflammatory treatments. Furthermore, assessment of the transcriptomics of epidermal cells upon IL-17 blockade also showed a restoration in the expression levels of pro-inflammatory cytokines. Importantly, reduction of other known epidermal aging traits was also observed, including pathways involved in oxidative stress functions and wound healing, highlighting the relevance of IL-17 in the development of age-associated traits in the skin. Lastly, aged mice treated with IL-17 neutralizing antibodies exhibited increased epidermal thickness and decreased cornified layer thickness compared to their adult counterparts, along with an improvement of the capacity of hair follicle growth upon epilation.  This suggests that IL-17 blockade in aged mice improves epidermal health, thus pinpointing the physiological relevance of IL-17 skin aging.

 

WHY I CHOSE THIS PREPRINT

In their preprint, Paloma Solá and colleagues provide a very comprehensive and detailed characterization on the types of skin cell populations that present altered transcriptomics associated to aging. Besides, their approach allowed them to identify that upregulated IL-17 in specific lymphoid cell subsets acts as the driver of the pro-inflammatory state associated to skin aging. In my opinion, the authors elegantly provide valuable and complex data in a very easy-to-follow manner, making evident the real impact of their study.  In fact, Paloma Solá and colleagues not only reveal a potential treatment to prevent unhealthy skin aging, but they also open the possibility to identify the exact molecular pathways that promote physiological skin aging.

 

MY QUESTIONS TO THE AUTHORS

  1. According to your data, there is a number of pro-inflammatory cytokines that show upregulated expression levels in different skin cell types of aged mice, including IL-6, IL-2, NFkB, and the STAT or TNF signaling pathways. Why did you focus on IL-17 signaling?
  2. If you performed a proof-of-concept experiment by providing adult mice with IL-17 in their skin, would you expect them to show accelerated skin aging?
  3. Considering your data on the anti-inflammatory effect that IL-17 blockade exerts in the skin niche, what is your speculation on the triggers of IL-17 upregulation in immune skin cells of aged mice?
  4. Does the IL-17 signaling from immune skin cells become systemic during aging? Could it be that IL-17 from other inflamed tissues is promoting its own regulation in the skin niche?
  5. Could enhanced IL-17 signaling be considered as a hallmark of autoimmune diseases?

 

REFERENCES

[1] López-Otín C., et al., The Hallmarks of Aging. Cell, 2013. doi: 10.1016/j.cell.2013.05.039

[2] Nestle FO., et al., Skin immune sentinels in health and disease. Nat Rev Immunol, 2009. doi: 10.1038/nri2622

[3] Ferrucci L and Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol, 2018. doi: 10.1038/s41569-018-0064-2

 

 

doi: https://doi.org/10.1242/prelights.31511

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Author's response

Paloma Solá shared

  1. We decided to focus on IL-17 signaling because both IL-17a and f were at the top of the list of upregulated genes during aging, which we obtained through 10X single cell sequencing. We observed this upregulation in specific lymphoid cells, which were showing a high proportion of gene expression and cell distribution changes during aging. Besides, when we started looking into the known role of IL-17 and its relevance in autoimmune and chronic inflammatory diseases such as psoriasis, we were intrigued to know if this cytokine could have a similar pro-inflammatory effect during aging. This could open the possibility of targeting IL-17 in order to decrease the appearance of age-associated traits in the skin.
  2. The most likely outcome of an excess of IL-17 in adult skin is the development of a chronic inflammatory disease similar to psoriasis, as it’s known that the increase of IL-17 signaling in the skin of these patients is one of the key factors that causes the development of lesions associated to the disease. These skin lesions show a much more aggravated phenotype to what occurs during aging, which lacks the development of such wounds. This is why a situation in which there is an increase in IL-17 signaling in the skin could lead to a diseased-like skin, which is not comparable to aged skin.
  3. It’s likely that IL-17 upregulation is due to an increase in a variety of age-associated pro-inflammatory signals. These signals can be caused due to a disruption of the aged epidermal protective layer, which allows the entry of external microorganisms into the skin. They could also be caused by stimuli trafficking from specific cell types or tissues, leading to an exacerbated secretion of pro-inflammatory signals that stimulate the polarization towards an IL-17 profile.  The combination of both these factors can be causing this skew towards an IL-17 secretory profile in lymphoid cells.
  4. We still haven’t fully determined how blocking of IL-17 affects aging in other tissues. Our speculation is that this effect will be restricted to the skin, as it’s exposed to external factors that can lead to the increase in pro-inflammatory signals that seem to be driven by IL-17 to some extent. However, it’s possible that the same signals that are causing the polarization of lymphoid cells towards IL-17 secretion are also trafficking to other organs. It would be interesting to check how much of these findings can be applied to other tissues in order to better understand how this IL-17 upregulation is occurring and how it affects systemic aging.
  5. It’s already known that there’s an increase of IL-17 signaling in autoimmune diseases. There are already existing treatments that target the development of these diseases by the use of neutralizing antibodies against IL-17A and/or F as well as their receptor, IL-17RA/RC. This has been shown to decrease disease burden in these patients, which is what led us to block IL-17a and f in aged skin following the same strategy, but during a prolonged time and while the mice age.

 

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