Cutting Edge: Divergent Cell-Specific Functions of MyD88 for Inflammatory Responses and Organ Injury in Septic Peritonitis

Gais, Peter; Reim, Daniel; Jusek, Gabriela; Rossmann-Bloeck, Tanja; Weighardt, Heike; Pfeffer, Klaus; Altmayr, Felicitas; Janssen, Klaus–Peter; Holzmann, Bernhard

doi:10.4049/jimmunol.1200038

Cited by 31 publications

(43 citation statements)

References 27 publications

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“…To investigate the role of DCs in IMQ-induced psoriasiform skin inflammation, we took advantage of a MyD88-inducible mouse strain (MyD88 LSL ), which enables Cre/loxP-mediated cell typespecific expression of the TLR-adaptor protein MyD88 on a MyD88-deficient background (14). Signaling via TLR7 is critically dependent on MyD88, and MyD88-deficient immune cells do not respond to IMQ (15).…”

Section: Resultsmentioning

confidence: 99%

“…Hence, we sought to investigate the role of CD11c + DCs to elicit psoriasiform skin inflammation. Using CD11c-Cre mice (19), we generated animals in which MyD88 was exclusively expressed in CD11c + DCs (DC-MyD88 ind ), whereas all other cells remained MyD88-deficient (14). Strikingly, DC-MyD88 ind and wild-type mice developed identical symptoms of psoriasiform skin disease following IMQ painting ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Langerin ^neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Wohn

Ober‐Blöbaum

Haak

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Psoriasis is an autoinflammatory skin disease of unknown etiology. Topical application of Aldara cream containing the Toll-like receptor (TLR)7 agonist Imiquimod (IMQ) onto patients induces flares of psoriasis. Likewise, in mice IMQ triggers pathological changes closely resembling psoriatic plaque formation. Key cytokines like IL-23 and type-I IFN (IFN-I), both being produced mainly by dendritic cells (DCs), have been implicated in psoriasis. Although plasmacytoid DCs (pDCs) are the main source of IFNα and thought to initiate disease, conventional DCs (cDCs) appear to maintain the psoriatic lesions. Any role of cDCs during lesion formation remains elusive. Here, we report that selective activation of TLR7 signaling specifically in CD11c + DCs was sufficient to induce psoriasiform skin disease in mice. Intriguingly, both pDCs and the IFN-I pathway were dispensable for the development of local skin inflammation. Selective TLR7 triggering of Langerin + DCs resulted in attenuated disease, whereas their depletion did not alter the severity of skin lesions. Moreover, after IMQ-painting, IL-23 was exclusively produced by Langerin neg DCs in vivo. In conclusion, TLR7-activated Langerin neg cDCs trigger psoriatic plaque formation via IL-23-mediated activation of innate IL-17/IL-22-producing lymphocytes, independently of pDCs or IFN-I. These results suggest therapeutic targeting of IL-23 production by cDCs to refine current treatment strategies for psoriasis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Langerin ^neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Wohn

Ober‐Blöbaum

Haak

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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163

169

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“…In these mice selective expression of MyD88 was obtained by crossing MyD88LSL mice, which carry a floxed transcriptional stop element between exons 1 and 2 [36] to Keratin 5-Cre mice [37]. Specific expression of MyD88 in whole skin [30] and in the epidermis of K5 ind MyD88 mice (Supporting Information Fig.…”

Section: Myd88 Signaling In Keratinocytes Controls Inflammation Durinmentioning

confidence: 99%

Requirement of MyD88 signaling in keratinocytes for Langerhans cell migration and initiation of atopic dermatitis‐like symptoms in mice

et al. 2016

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Atopic dermatitis (AD) is a chronic inflammatory disease controlled by the innate and adaptive immune system. To elucidate the impact of innate immune signaling in AD, we analyzed MyD88-deficient mice in a murine model of AD-like dermatitis by epicutaneous sensitization with ovalbumin (OVA). Global MyD88 deficiency led to reduced epidermal thickening and diminished accumulation of macrophages within the inflamed skin. In addition, we observed impaired emigration of Langerhans cells (LCs) out of the epidermis of MyD88-deficient mice. These findings indicate that MyD88 deficiency affects various skin-resident cell types in the AD model. Moreover, production of IFN-g, IL-17, and CCL17 was reduced in skin draining lymph node cells and OVA-specific immunoglobulin levels were lower in MyD88-deficient mice. We further investigated the role of MyD88 in keratinocytes, as keratinocytes contribute to AD pathology. Exclusive expression of MyD88 in epidermal keratinocytes partially restored LC emigration after AD induction and expression of CCL17 in skin draining lymph nodes (LNs), but did not promote epidermal thickening nor production of IL-17. Altogether, these data demonstrate that MyD88 signaling in keratinocytes is able to restore LC migration in an otherwise MyD88-deficient background, and significantly contributes to the development of AD-like dermatitis.Keywords: Allergology r Dermatitis r Innate immunity r Langerhans cells r MyD88 signaling r Skin inflammation Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAtopic dermatitis (AD) is a chronic, inflammatory skin disease [1,2] characterized by pruritic, scaly, and erythematous skin lesions and is caused by genetic, environmental, and immunologic factors Correspondence: Dr. Heike Weighardt e-mail: Heike.weighardt@uni-bonn.de [3]. Activation of the immune system during AD results in a mixed Th1 and Th2 response, but also Th22 and Th17 subsets contribute to the immune response [4]. In the majority of AD patients the disease is associated with the development of allergen-specific IgE titers, however also a non-IgE-associated form exists [2]. * These authors contributed equally to this work.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 982Sonja Didovic et al. Eur. J. Immunol. 2016. 46: 981-992 The development of AD involves barrier defects caused by mutations in structural genes such as filaggrin or disturbed protease activity in the epidermis [5,6] and a dysregulation of the immune system of the skin [6,7]. Impaired barrier function is characterized by enhanced transepidermal water loss (TEWL), which may enhance entry of pathogens, allergens, or toxins and thereby facilitate activation of the skin immune system [6,7]. The skin dendritic cell (DC) network comprises epidermal Langerhans cells (LCs) and different subsets of dermal DCs (dDCs) [8,9]. Upon antigen acquisition both LCs and dDCs get activated and migrate to the draining lymph nodes (LNs) to induce an immune re...

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“…16 Crossing Myd88 LSL/LSL mice with pvillin-Cre 17 mice and LysM-Cre mice 18 lead to excision of the intron-gene-trap and therefore re-expression of Myd88 on mRNA and protein level (Fig. 1C) in intestinal epithelial ( Myd88 IEC ) or myeloid cells (bone marrow derived macrophages, Myd88 MYEL ; for a schematic representation of the mouse strains refer to Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Incubation with TLR-ligands in vitro, as well as ELISA assays for cytokine production were carried out as described in detail earlier. 16 …”

Section: Methodsmentioning

confidence: 99%

Cell-type specific MyD88 signaling is required for intestinal tumor initiation and progression to malignancy

Holtorf

Conrad²,

Holzmann³

et al. 2018

OncoImmunology

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The signal adapter MyD88, an essential component of Toll-like receptor (TLR) signaling, is important for gut-microbiome interactions. However, its contribution to cancer and its cell-type specific functions are controversially discussed. Therefore, we generated new tissue-specific mouse models and analyzed the clinical importance in human colorectal cancer. A gene-trap was inserted into the murine Myd88 gene (Myd88LSL), yielding MyD88-deficient background with Cre-mediated re-expression in myeloid (MYEL) or intestinal epithelial cells (IECs). These lines were bred with the Apc1638N model that develops invasive adenocarcinoma and analyzed at 12 months. Further, two patient collectives of colorectal cancer (n = 61, and n = 633) were analyzed for expression of Myd88 and TLRs. MyD88 expression was significantly increased in carcinomas, and increased intratumoral levels of MyD88 and TLR pathway components were associated with significantly shorter disease-free (P = .011), and overall survival (P < .0001). In accordance, fully MyD88-deficient mice showed highly significantly decreased tumor incidence, tumor numbers, increased survival, and, importantly, fully lacked malignant lesions. Thus, MyD88 is essential for tumorigenesis and especially progression to malignancy. Tissue-specific re-expression of MyD88 highly significantly increased tumor initiation by differing mechanisms. In intestinal epithelia, MyD88 enhanced epithelial turnover, whereas in myeloid cells, it led to increased production of tumor- and stemness-enhancing cytokines, significantly associated with altered expression of adaptive immune genes. However, neither re-expression of MyD88 in IECs or myeloid cells was sufficient for malignant progression to carcinoma. Thus, MyD88 crucially contributes to colorectal cancer initiation and progression with non-redundant and cell-type specific functions, constituting an attractive therapeutic target.

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Cutting Edge: Divergent Cell-Specific Functions of MyD88 for Inflammatory Responses and Organ Injury in Septic Peritonitis

Cited by 31 publications

References 27 publications

Langerin ^neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Langerin ^neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Requirement of MyD88 signaling in keratinocytes for Langerhans cell migration and initiation of atopic dermatitis‐like symptoms in mice

Cell-type specific MyD88 signaling is required for intestinal tumor initiation and progression to malignancy

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Cutting Edge: Divergent Cell-Specific Functions of MyD88 for Inflammatory Responses and Organ Injury in Septic Peritonitis

Cited by 31 publications

References 27 publications

Langerin neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Langerin neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Requirement of MyD88 signaling in keratinocytes for Langerhans cell migration and initiation of atopic dermatitis‐like symptoms in mice

Cell-type specific MyD88 signaling is required for intestinal tumor initiation and progression to malignancy

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Langerin ^neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Langerin ^neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice