Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Jan 15;198(2):767-775.
doi: 10.4049/jimmunol.1601551. Epub 2016 Dec 5.

MCPIP1/Regnase-1 Restricts IL-17A- and IL-17C-Dependent Skin Inflammation

Leticia Monin  1 , Johann E Gudjonsson  2 , Erin E Childs  1 , Nilesh Amatya  1 , Xianying Xing  2 , Akash H Verma  1 , Bianca M Coleman  1 , Abhishek V Garg  1 , Meaghan Killeen  3 , Alicia Mathers  3 , Nicole L Ward  4 , Sarah L Gaffen  5
Affiliations

MCPIP1/Regnase-1 Restricts IL-17A- and IL-17C-Dependent Skin Inflammation

Leticia Monin et al. J Immunol. .

Abstract

The IL-17 family cytokines IL-17A and IL-17C drive the pathogenesis of psoriatic skin inflammation, and anti-IL-17A Abs were recently approved to treat human psoriasis. Little is known about mechanisms that restrain IL-17 cytokine-mediated signaling, particularly IL-17C. In this article, we show that the endoribonuclease MCP-1-induced protein 1 (MCPIP1; also known as regnase-1) is markedly upregulated in human psoriatic skin lesions. Similarly, MCPIP1 was overexpressed in the imiquimod (IMQ)-driven mouse model of cutaneous inflammation. Mice with an MCPIP1 deficiency (Zc3h12a+/-) displayed no baseline skin inflammation, but they showed exacerbated pathology following IMQ treatment. Pathology in Zc3h12a+/- mice was associated with elevated expression of IL-17A- and IL-17C-dependent genes, as well as with increased accumulation of neutrophils in skin. However, IL-17A and IL-17C expression was unaltered, suggesting that the increased inflammation in Zc3h12a+/- mice was due to enhanced downstream IL-17R signaling. Radiation chimeras demonstrated that MCPIP1 in nonhematopoietic cells is responsible for controlling skin pathology. Moreover, Zc3h12a+/-Il17ra-/- mice given IMQ showed almost no disease. To identify which IL-17RA ligand was essential, Zc3h12a+/-Il17a-/- and Zc3h12a+/-Il17c-/- mice were given IMQ; these mice had reduced but not fully abrogated pathology, indicating that MCPIP1 inhibits IL-17A and IL-17C signaling. Confirming this hypothesis, Zc3h12a-/- keratinocytes showed increased responsiveness to IL-17A and IL-17C stimulation. Thus, MCPIP1 is a potent negative regulator of psoriatic skin inflammation through IL-17A and IL-17C. Moreover, to our knowledge, MCPIP1 is the first described negative regulator of IL-17C signaling.

PubMed Disclaimer

Figures

Figure 1
Figure 1. MCPIP1 expression is elevated in human psoriasis
(A) ZC3H12A expression in normal healthy skin (NN), or non-lesional (PN) and paired lesional (PP) skin samples from psoriasis patients (n=9–10) was determined by qPCR. Expression was normalized to RPLP0. (B) MCPIP1 expression was detected by immunohistochemistry in formalin-fixed, paraffin embedded (FFPE) sections from normal healthy skin (NN), uninvolved (PN) and involved (PP) psoriasis skin **p<0.01, Mann-Whitney test. Scale bar = 100 μm.
Figure 2
Figure 2. MCPIP1 expression is elevated in IMQ-driven dermatitis and limits disease severity
C57BL/6 (WT) mice (n=3/date) were treated topically on dorsal skin with IMQ days 0–4. Expression of (A) Zc3h12a, (B) Il17a and (C) Il17c in skin was determined by qPCR. (D) Expression of the indicated genes was determined by qPCR in untreated Zc3h12a+/+ (WT), Zc3h12a+/− and Zc3h12a−/− skin. (E) Cutaneous neutrophil infiltration was analyzed in skin by flow cytometry and % neutrophils in CD45+ gate is shown. (F) WT or Zc3h12a+/− mice (n=3–5 per day) were treated topically with mock cream or IMQ on days 0–4. Gross skin pathology for a representative animal at day 3 is shown. (G) Change in ear thickness between treated and mock-treated ears was assessed daily in the indicated mice. (H) Representative images of H&E-stained FFPE mouse skin sections on day 3 (x200). Scale bar, 200μm. *p<0.05, Mann-Whitney test.
Figure 3
Figure 3. MCPIP1-deficient mice exhibit increased neutrophil infiltration and expression of IL-17 gene targets upon IMQ treatment
The indicated mice (n=5–8) were treated topically with IMQ daily. (A) IL-17 production in dermal γδ T cells was determined by flow cytometry. % of IL-17A+ cells within the CD45+γδ-TCRint lymphocyte gate is shown. (B) Expression of the indicated genes in dorsal skin was determined by qPCR. (C) Neutrophil infiltration in skin was evaluated by flow cytometry and % neutrophils in CD45+ gate is shown. (D) Expression of the indicated genes was determined by qPCR. *p<0.05, Mann-Whitney test.
Figure 4
Figure 4. Elevated IMQ-induced inflammation in MCPIP1-deficient mice is due to both IL-17A and IL-17C signaling
The indicated mice were treated topically with control cream or IMQ on days 0, 1 and 2. (A) Skin neutrophil infiltration was determined by flow cytometry and % neutrophils in CD45+ gate is shown. (n=3–18). Data are pooled from 4 independent experiments. (B–E) Expression of the indicated genes was determined by qPCR. (n=3–10). Data are pooled from 2 independent experiments. *p<0.05, **p<0.01, ***p<0.001, Mann-Whitney test. ns-not significant.
Figure 5
Figure 5. MCPIP1-dependent exacerbation of IMQ-driven dermatitis occurs through resident skin cells and is associated with elevated IL-17A and IL-17C signaling in keratinocytes
WT or Zc3h12a+/− mice (n=4–9) were lethally irradiated and reconstituted with WT or Zc3h12a+/− bone marrow. After 6 weeks to allow immune reconstitution, mice were treated topically with control cream or IMQ and analyzed on days 0, 1 or 2. (A) Skin neutrophil infiltration was determined by flow cytometry and % neutrophils in CD45+ gate is shown. (B–F) Primary mouse WT (gray) or Zc3h12a−/− (black) neonatal KCs were treated for 16 h with IL-17A or IL-17C, and expression of indicated genes was assessed by qPCR (n=3–5). **p<0.01, ns-not significant, Mann-Whitney test.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Gaffen SL, Jain R, Garg AV, Cua DJ. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol. 2014;14:585–600. - PMC - PubMed
    1. Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CE, Papp K, Puig L, Nakagawa H, Spelman L, Sigurgeirsson B, Rivas E, Tsai TF, Wasel N, Tyring S, Salko T, Hampele I, Notter M, Karpov A, Helou S, Papavassilis C, Group ES, Group FS. Secukinumab in plaque psoriasis--results of two phase 3 trials. N Engl J Med. 2014;371:326–338. - PubMed
    1. Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, Antoni C, Draelos Z, Gold MH, Durez P, Tak PP, Gomez-Reino JJ, Foster CS, Kim RY, Samson CM, Falk NS, Chu DS, Callanan D, Nguyen QD, Rose K, Haider A, Di Padova F G Psoriasis Study, G Rheumatoid Arthritis Study, G Uveitis Study. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med. 2010;2:52ra72. - PubMed
    1. Sonnenberg GF, Artis D. Innate lymphoid cells in the initiation, regulation and resolution of inflammation. Nat Med. 2015;21:698–708. - PMC - PubMed
    1. Cua DJ, Tato CM. Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol. 2010;10:479–489. - PubMed

Publication types