Alarmin Cytokines as Central Regulators of Cutaneous Immunity

Hasegawa, Tatsuya; Oka, Tomonori; Demehri, Shadmehr

doi:10.3389/fimmu.2022.876515

Cited by 26 publications

(11 citation statements)

References 199 publications

(218 reference statements)

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“…TSLP has been previously identified as one of three principal alarmins produced by epithelial cells and stromal cells in response to insults at barrier surfaces 33 . In the skin, TSLP production by epidermal keratinocytes can be induced by mechanical injury, environmental allergens, and cutaneous pathogens such as Staphylococcus aureus 23 .…”

Section: Discussionmentioning

confidence: 99%

Dermis resident macrophages orchestrate localized ILC2-eosinophil circuitries to maintain their M2-like properties and promote non-healing cutaneous leishmaniasis

Sacks

Kang

Kamenyeva³

et al. 2023

Preprint

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Tissue-resident macrophages (TRMs) are critical for tissue homeostasis/repair. We previously showed that dermal TRMs produce CCL24 (eotaxin2) which mediates their interaction with IL-4 producing eosinophils, required to maintain their number and M2-like properties in the TH1 environment of the Leishmania major infected skin. Here, we unveil another layer of TRM self-maintenance involving their production of TSLP, an alarmin typically characterized as epithelial cell-derived. Both TSLP signaling and IL-5+ innate lymphoid cell 2 (ILC2s) were shown to maintain the number of dermal TRMs and promote infection. Single cell RNA sequencing identified the dermal TRMs as the sole source of TSLP and CCL24. Development of Ccl24-cre mice permitted specific labeling of dermal TRMs, as well as interstitial TRMs from other organs. Genetic ablation of TSLP from dermal TRMs reduced the number of dermal TRMs, and disease was ameliorated. Thus, by orchestrating localized type 2 circuitries with ILC2s and eosinophils, dermal TRMs are self-maintained as a replicative niche for L. major.

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Section: Discussionmentioning

confidence: 99%

Dermis resident macrophages orchestrate localized ILC2-eosinophil circuitries to maintain their M2-like properties and promote non-healing cutaneous leishmaniasis

Sacks

Kang

Kamenyeva³

et al. 2023

Preprint

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“…IL-1β was shown to induce the expression of K6a (Komine et al, 2001), while additionally activating transcription factor NF-κB, which can cause the downregulation of filaggrin and loricrin expression (Michaelidou et al, 2023). Moreover, mRNA levels of Tslp , a master regulator of type II skin immunity (Hasegawa et al 2022), were also vastly elevated (Fig. 2J).…”

Section: To the Editormentioning

confidence: 99%

Novel, postnatal manifestation of an epidermal barrier defect in a mouse model of isolated sulfite oxidase deficiency

Johannes,

Rübsam,

Löhr

et al. 2024

Preprint

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Sulfite oxidase deficiency is a rare inborn error in metabolism leading to early childhood death due to rapidly progressing neurodegeneration. A new mouse model of sulfite oxidase deficiency carrying a homozygous deletion in the Suox gene resembles the human pathology in terms of neonatal death and elevation of sulfite and thiosulfate in plasma and urine, respectively. Homozygous Suox-/- mice are initially born healthy, display growth retardation starting at postnatal day 4 and die in average at day 9.6. Here we report that Suox-/- mice develop dry and scaly skin early postnatally, showing that sulfite oxidase is essential to maintain a functional skin barrier after birth. At postnatal day 5 Suox-/- mice develop altered epidermal morphology and dysregulated early and late keratinocyte differentiation accompanied by increased stress response. We propose a sulfite-induced cleavage of disulfide bonds in key epidermal proteins essential for a functional barrier.

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“…The barrier dysfunction that occurs in the early stages of AD facilitates the penetration of allergens into the skin, and damaged keratinocytes produce cytokines such as TSLP, IL-25, and IL-33. These cytokines activate Th2 cells and ILC2s, leading to the production of Th2 cytokines ( 9 ). Additionally, TSLP matures Langerhans cells (LCs) in the epidermis and induces Th2 cells ( 10 ).…”

Section: Non-lesional Skinmentioning

confidence: 99%

Interplay of cytokines in the pathophysiology of atopic dermatitis: insights from Murin models and human

Yamamura,

Nakashima,

Otsuka

2024

Front. Med.

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The pathogenesis of atopic dermatitis (AD) is understood to be crucially influenced by three main factors: dysregulation of the immune response, barrier dysfunction, and pruritus. In the lesional skin of AD, various innate immune cells, including Th2 cells, type 2 innate lymphoid cells (ILC2s), and basophils, produce Th2 cytokines [interleukin (IL)-4, IL-5, IL-13, IL-31]. Alarmins such as TSLP, IL-25, and IL-33 are also produced by epidermal keratinocytes, amplifying type 2 inflammation. In the chronic phase, not only Th2 cells but also Th22 and Th17 cells increase in number, leading to suppression of filaggrin expression by IL-4, IL-13, and IL-22, which further deteriorates the epidermal barrier function. Dupilumab, which targets IL-4 and IL-13, has shown efficacy in treating moderate to severe AD. Nemolizumab, targeting IL-31RA, effectively reduces pruritus in AD patients. In addition, clinical trials with fezakinumab, targeting IL-22, have demonstrated promising results, particularly in severe AD cases. Conversely, in murine models of AD, several cytokines, initially regarded as promising therapeutic targets, have not demonstrated sufficient efficacy in clinical trials. IL-33 has been identified as a potent activator of immune cells, exacerbating AD in murine models and correlating with disease severity in human patients. However, treatments targeting IL-33 have not shown sufficient efficacy in clinical trials. Similarly, thymic stromal lymphopoietin (TSLP), integral to type 2 immune responses, induces dermatitis in animal models and is elevated in human AD, yet clinical treatments like tezepelumab exhibit limited efficacy. Therapies targeting IL-1α, IL-5, and IL-17 also failed to achieve sufficient efficacy in clinical trials. It has become clear that for treating AD, IL-4, IL-13, and IL-31 are relevant therapeutic targets during the acute phase, while IL-22 emerges as a target in more severe cases. This delineation underscores the necessity of considering distinct pathophysiological aspects and therapeutic targets in AD between mouse models and humans. Consequently, this review delineates the distinct roles of cytokines in the pathogenesis of AD, juxtaposing their significance in human AD from clinical trials against insights gleaned from AD mouse models. This approach will improve our understanding of interspecies variation and facilitate a deeper insight into the pathogenesis of AD in humans.

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Alarmin Cytokines as Central Regulators of Cutaneous Immunity

Cited by 26 publications

References 199 publications

Dermis resident macrophages orchestrate localized ILC2-eosinophil circuitries to maintain their M2-like properties and promote non-healing cutaneous leishmaniasis

Dermis resident macrophages orchestrate localized ILC2-eosinophil circuitries to maintain their M2-like properties and promote non-healing cutaneous leishmaniasis

Novel, postnatal manifestation of an epidermal barrier defect in a mouse model of isolated sulfite oxidase deficiency

Interplay of cytokines in the pathophysiology of atopic dermatitis: insights from Murin models and human

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