CX3CR1 deficiency attenuates imiquimod-induced psoriasis-like skin inflammation with decreased M1 macrophages

Morimura, Sohshi; Oka, Tomonori; Sugaya, Makoto; Sato, Shinichi

doi:10.1016/j.jdermsci.2016.03.004

Cited by 41 publications

(40 citation statements)

References 35 publications

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“…Moreover, dermal resident macrophages were shown to express IL10 under steady-state condition thus playing an anti-inflammatory and scavenging role in the skin (Tamoutounour et al, 2013). However, under inflammatory conditions, monocytederived macrophages infiltrate the skin and support the production of cytokines like TNFa, IL-6, IL-12 and IFNs (Chen et al, 2015;Drobits et al, 2012;Morimura et al, 2016;Terhorst et al, 2015). Injury-induced CCL2 production by the skin was recently shown to induce macrophage infiltration and TNFα production, ultimately resulting in hair cycle induction (Chen et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Effects of Imiquimod on Hair Follicle Stem Cells and Hair Cycle Progression

Amberg

Holcmann

Stulnig

et al. 2016

Journal of Investigative Dermatology

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Topical imiquimod (IMQ) application is widely used as a model for psoriasiform-like skin inflammation in mice. Although the effects on the epidermis are well characterized, it is unclear how IMQ affects hair follicles and cycling. Here we investigated how IMQ affects hair follicle stem cells and whether the timing of IMQ application influences the immune infiltrate. Our results show that IMQ application at mid and late telogen activated hair follicle stem cells leading to premature hair cycle entry (anagen), which was accompanied by massive infiltration of inflammatory macrophages and gamma delta T cells, whereas the number of the respective resident populations decreased. Interestingly, high resident macrophage numbers were present in Rag2 mice and were maintained after IMQ treatment explaining why IMQ-induced anagen was reduced. This could be rescued after macrophage depletion suggesting that resident macrophages inhibit whereas inflammatory infiltrating macrophages stimulate hair follicle stem cell activation. The expression of the anagen-inhibiting factor BMP-4 was reduced by IMQ treatment as well as the activating factors Wnt showing that IMQ-induced hair follicle stem cell activation occurs by a Wnt-independent mechanism involving inflammatory cytokines such as CCL2 and TNF-α. On the basis of our findings, we recommend conducting experiments with IMQ during mid and late telogen as the biggest differences in immune cell composition are observed.

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Section: Discussionmentioning

confidence: 99%

Effects of Imiquimod on Hair Follicle Stem Cells and Hair Cycle Progression

Amberg

Holcmann

Stulnig

et al. 2016

Journal of Investigative Dermatology

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“…Pro‐inflammatory activities of macrophages is crucial in psoriasis. The M1 macrophage genomic signature is overexpressed in psoriasis, and CX3CR1 deficiency in mice resulted in attenuated imiquimod‐induced psoriasiform inflammation by shifting the M1/M2 polarization balance towards the M2 phenotype . Moreover, macrophage‐derived tumor necrosis factor‐α (TNF‐α) may be involved in the induction of systemic inflammation that links psoriasis and comorbidities .…”

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confidence: 99%

“…Moreover, macrophage‐derived tumor necrosis factor‐α (TNF‐α) may be involved in the induction of systemic inflammation that links psoriasis and comorbidities . However, psoriasis is primarily mediated by the interleukin (IL)‐23/Th17 pathway . Typical Th17‐mediated immune diseases involving various tissues include multiple sclerosis (MS) and its animal model (experimental autoimmune encephalomyelitis [EAE]), inflammatory bowel diseases, rheumatoid arthritis and the psoriasis, which all show a M1 predominance .…”

mentioning

confidence: 99%

“…TNF‐α, one of the key mediators of psoriasis, negatively regulated STAT6‐dependent M2 gene expression, and TNF receptor signaling was essential for the expression of M1 genes . Furthermore, M1 macrophages produced pro‐inflammatory cytokines, including IL‐1β, TNF‐α, IL‐6 and IL‐23, while M2 macrophages produced anti‐inflammatory IL‐10 and attenuated Th1 activation . Because RGC‐32 can influence M1 and M2 macrophage polarization by inhibiting the former and promoting the latter, reduced expression of RGC‐32 in psoriasis could enhance the pro‐inflammatory microenvironment in psoriasis …”

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confidence: 99%

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Decreased expression of response gene to complement 32 in psoriasis and its association with reduced M2 macrophage polarization

Kim

Jang

Lee

et al. 2019

The Journal of Dermatology

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“…These results suggest that macrophages with a heterogeneous M1/M2 phenotype were activated in the IMQ-treated skin of adaptive Th17-induced inflammation. Morimura et al also recently reported that CX3CR1 + macrophages were partially involved in the IMQ-induced skin inflammation 32 , suggesting the importance of macrophage activity in this psoriasis mouse model.…”

Section: Discussionmentioning

confidence: 63%

001 IL-17A induces heterogeneous macrophages, and it does not alter the effects of lipopolysaccharides on macrophage activation in the skin of mice

Nakai

Haba

et al. 2018

Journal of Investigative Dermatology

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Macrophages are central to inflammatory response and become polarized towards the M1 or M2 states upon activation by immunostimulants. In this study, we investigated the effects of lipopolysaccharides (LPS) and interleukin (IL)-In skin, various immune cells are activated by invading pathogens or skin damage. Macrophages are vital to innate immunity, and their activation leads to an increased capacity to regulate other cells through the release of cytokines and chemokines that is induced in adaptive immunity 1 . Persistent macrophage activity results in the development of chronic inflammatory skin diseases such as psoriasis and atopic dermatitis (AD) 2 . Abnormal immune conditions of tissues affects the activation and plasticity/polarization of macrophages (i.e. their maturation towards the M1 or M2 state) 3 . The classical pathway is defined as the interferon (IFN)-γ-dependent activation of M1 type macrophages by T helper 1 (Th1)-type responses. The alternative pathway is defined as the M2 type macrophage activation by Th2-type cytokines interleukin (IL)-4, IL-6, IL-10 and IL-13. However, recent studies have shown that the macrophage lineages are diverse and heterogeneous as demonstrated by the presence of unique M1/M2 heterogeneous macrophages in IL-17 immunity.IL-17 family members play an active role in inflammatory diseases and autoimmune diseases 4 . IL-17A is the prototype pro-inflammatory cytokine of the IL-17 family 5 , which is largely produced by activated memory T lymphocytes, and functions to stimulate innate immunity. A well-known IL-17A-related skin disease is psoriasis. The association between IL-17A and psoriasis is well established in humans, mouse and in vitro models 6 . The roles of IL-17A are also implicated in the pathogenesis of AD 7,8 . IL-17A is highly expressed in flaky-tail (Flg ft ) mouse, a murine AD model, that carries mutations in the filaggrin gene 9,10 . Moreover, IL-17A is involved in infectious, inflammatory, neutrophilic, granulomatous, bullous and malignant skin diseases 11 . However, there are few reports regarding the direct effects of IL-17A on the macrophage function in the skin.

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CX3CR1 deficiency attenuates imiquimod-induced psoriasis-like skin inflammation with decreased M1 macrophages

Cited by 41 publications

References 35 publications

Effects of Imiquimod on Hair Follicle Stem Cells and Hair Cycle Progression

Effects of Imiquimod on Hair Follicle Stem Cells and Hair Cycle Progression

Decreased expression of response gene to complement 32 in psoriasis and its association with reduced M2 macrophage polarization

001 IL-17A induces heterogeneous macrophages, and it does not alter the effects of lipopolysaccharides on macrophage activation in the skin of mice

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