Dataset Information

TLR2 Signaling in Skin Nonhematopoietic Cells Induces Early Neutrophil Recruitment in Response to Leishmania major Infection.

ABSTRACT: Neutrophils are rapidly recruited to the mammalian skin in response to infection with the cutaneous Leishmania pathogen. The parasites use neutrophils to establish the disease; however, the signals driving early neutrophil recruitment are poorly known. Here, we identified the functional importance of TLR2 signaling in this process. Using bone marrow chimeras and immunohistology, we identified the TLR2-expressing cells involved in this early neutrophil recruitment to be of nonhematopoietic origin. Keratinocytes are damaged and briefly in contact with the parasites during infection. We show that TLR2 triggering by Leishmania major is required for their secretion of neutrophil-attracting chemokines. Furthermore, TLR2 triggering by L. major phosphoglycans is critical for neutrophil recruitment to negatively affect disease development, as shown by better control of lesion size and parasite load in Tlr2^-/- compared with wild-type infected mice. Conversely, restoring early neutrophil presence in Tlr2^-/- mice through injection of wild-type neutrophils or CXCL1 at the onset of infection resulted in delayed disease resolution comparable to that observed in wild-type mice. Taken together, our data show a crucial role for TLR2-expressing nonhematopoietic skin cells in the recruitment of the first wave of neutrophils after L. major infection, a process that delays disease control.

SUBMITTER: Ronet C

PROVIDER: S-EPMC8024985 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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TLR2 Signaling in Skin Nonhematopoietic Cells Induces Early Neutrophil Recruitment in Response to Leishmania major Infection.

Ronet Catherine C Passelli Katiuska K Charmoy Mélanie M Scarpellino Leo L Myburgh Elmarie E Hauyon La Torre Yazmin Y Turco Salvatore S Mottram Jeremy C JC Fasel Nicolas N Luther Sanjiv A SA Beverley Stephen M SM Launois Pascal P Tacchini-Cottier Fabienne F

The Journal of investigative dermatology 20181227 6

Neutrophils are rapidly recruited to the mammalian skin in response to infection with the cutaneous Leishmania pathogen. The parasites use neutrophils to establish the disease; however, the signals driving early neutrophil recruitment are poorly known. Here, we identified the functional importance of TLR2 signaling in this process. Using bone marrow chimeras and immunohistology, we identified the TLR2-expressing cells involved in this early neutrophil recruitment to be of nonhematopoietic origin ...[more]

PMID: 30594488

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Project description:IntroductionThe skin immune system is tightly regulated to prevent inappropriate inflammation in response to harmless environmental substances. This regulation is actively maintained by mechanisms including cytokines and cell surface receptors and its loss results in inflammatory disease. In the case of psoriasis, inappropriate immune activation leads to IL-17-driven chronic inflammation, but molecular mechanisms underlying this loss of regulation are not well understood. Immunoglobulin family member CD200 and its receptor, CD200R1, are important regulators of inflammation. Therefore, we determined if this pathway is dysregulated in psoriasis, and how this affects immune cell activity.MethodsHuman skin biopsies were examined by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. The role of CD200R1 in regulating psoriasis-like skin inflammation was examined using CD200R1 blocking antibodies in mouse psoriasis models. CD200R1 blocking antibodies were also used in an in vivo neutrophil recruitment assay and in vitro assays to examine macrophage, innate lymphoid cell, γδ T cell, and neutrophil activity.ResultsWe reveal that CD200 and signaling via CD200R1 are reduced in non-lesional psoriasis skin. In mouse models of psoriasis CD200R1 was shown to limit psoriasis-like inflammation by enhancing acanthosis, CCL20 production and neutrophil recruitment, but surprisingly, macrophage function and IL-17 production were not affected, and neutrophil reactive oxygen species production was reduced.ConclusionCollectively, these data show that CD200R1 affects neutrophil function and limits inflammatory responses in healthy skin by restricting neutrophil recruitment. However, the CD200 pathway is reduced in psoriasis, resulting in a loss of immune control, and increased neutrophil recruitment in mouse models. In conclusion, we highlight CD200R1:CD200 as a pathway that might be targeted to dampen inflammation in patients with psoriasis.

Dataset Information

TLR2 Signaling in Skin Nonhematopoietic Cells Induces Early Neutrophil Recruitment in Response to Leishmania major Infection.

Publications

TLR2 Signaling in Skin Nonhematopoietic Cells Induces Early Neutrophil Recruitment in Response to Leishmania major Infection.

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