Chronic dermatitis is a hallmark of Dedicator of cytokinesis 8 (DOCK8) deficiency. The migration of DOCK8-deficient T cells to the skin and their survival there have been reported to be defective. ...Surprisingly, we found that Dock8−/− mice demonstrated an exaggerated contact hypersensitivity (CHS) response to oxazolone with increased ear swelling, T-cell infiltration, and expression of Ifng. To understand the mechanisms of persistent skin inflammation in DOCK8 deficiency, we examined mice with selective deficiency of DOCK8 in T cells or T regulatory cells (Tregs) and found that both have exaggerated CHS. Moreover, oral tolerance to oxazolone, mediated by Tregs, was impaired in Dock8−/− mice. Transfer of Tregs from oxazolone-sensitized wild-type mice, but not Dock8−/− mice, reduced the CHS response of Dock8−/− recipients. Lack of DOCK8 in Tregs resulted in their acquisition of a pathogenic FOXP3+T-bet+IFNγ+ phenotype at CHS sites and promoted their conversion into ex-Tregs. The transfer of Tregs from Dock8−/− mice increased the CHS response of wild-type recipients to oxazolone. Thus, DOCK8 expression in Tregs limits CHS by promoting Treg stability and fitness in inflamed skin. Interventions aimed at ameliorating Treg function may be useful in treating skin inflammation in DOCK8 deficiency.
Atopic dermatitis (AD) is characterized by a skin barrier defect aggravated by mechanical injury inflicted by scratching, a T
2 cell-dominated immune response, and susceptibility to viral skin ...infections that are normally restrained by a T
1 cell response. The signals leading to a T
2 cell-dominated immune response in AD are not completely understood.
Our aim was to determine the role of IL-13 in initiation of the T
cell response to cutaneously encountered antigens.
Wild-type, Il13
, Il1rl1
, and Il4ra
mice, as well as mice with selective deficiency of IL-13 in mast cells (MCs) were studied; in addition, dendritic cells (DCs) purified from the draining lymph nodes of tape-stripped and ovalbumin (OVA)-sensitized skin were examined for their ability to polarize naive OVA-TCR transgenic CD4
T cells. Cytokine expression was examined by reverse-transcriptase quantitative PCR, intracellular flow cytometry, and ELISA. Contact hypersensitivity to dinitrofluorobenzene was examined.
Tape stripping caused IL-33-driven upregulation of Il13 expression by skin MCs. MC-derived IL-13 acted on DCs from draining lymph nodes of OVA-sensitized skin to selectively suppress their ability to polarize naive OVA-TCR transgenic CD4
T cells into IFN-γ-secreting cells. MC-derived IL-13 inhibited the T
1 cell response in contact hypersensitivity to dinitrofluorobenzene. IL-13 suppressed IL-12 production by mouse skin-derived DCs in vitro and in vivo. Scratching upregulated IL13 expression in human skin, and IL-13 suppressed the capacity of LPS-stimulated human skin DCs to express IL-12 and promote IFN-γ secretion by CD4
T cells.
Release of IL-13 by cutaneous MCs in response to mechanical skin injury inhibits the T
1 cell response to cutaneous antigen exposure in AD.
Elucidating the mechanisms that sustain asthmatic inflammation is critical for precision therapies. We found that interleukin-6- and STAT3 transcription factor-dependent upregulation of Notch4 ...receptor on lung tissue regulatory T (T
) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted T
cells into the type 2 and type 17 helper (T
2 and T
17) effector T cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced growth and differentiation factor 15 expression in T
cells, which activated group 2 innate lymphoid cells to provide a feed-forward mechanism for aggravated inflammation. Notch4, Wnt and Hippo were upregulated in circulating T
cells of individuals with asthma as a function of disease severity, in association with reduced T
cell-mediated suppression. Our studies thus identify Notch4-mediated immune tolerance subversion as a fundamental mechanism that licenses tissue inflammation in asthma.
Mechanical skin injury causes IL-33-driven upregulation of
Il13
expression by MCs, which selectively suppresses IL-12 production by skin-derived DCs restraining their ability to polarize naïve CD4
+
...T cells into Th1 cells.
Chronic dermatitis is a hallmark of Dedicator of cytokinesis 8 (DOCK8) deficiency. The migration of DOCK8-deficient T cells to the skin and their survival there has been reported to be defective. ...Surprisingly, we found that
Dock8
−/−
mice demonstrated an exaggerated contact hypersensitivity (CHS) response to oxazolone (OXA) with increased ear swelling, T cell infiltration and expression of
Ifng
. To understand the mechanisms of persistent skin inflammation in DOCK8 deficiency, we examined mice with selective deficiency of DOCK8 in T cells or T regulatory cells (Tregs) and found that both have exaggerated CHS. Moreover, oral tolerance to OXA, mediated by Tregs, was impaired in
Dock8
−/−
mice. Transfer of Tregs from OXA-sensitized WT, but not
Dock8
−/−
, mice reduced the CHS response of
Dock8
−/−
recipients. Lack of DOCK8 in Tregs resulted in their acquisition of a pathogenic FOXP3
+
T-bet
+
IFNγ
+
phenotype at CHS sites and promoted their conversion into ex-Treg cells. Transfer of Tregs from
Dock8
−/−
mice increased the CHS response of WT recipients to OXA. Thus, DOCK8 expression in Tregs limits CHS by promoting Treg cell stability and fitness in inflamed skin. Interventions aimed at ameliorating Treg function may be useful in treating skin inflammation in DOCK8 deficiency.
In a new article published in JID Innovations, Nakatani-Kusakabe et al. (2021) show that type 2 innate lymphoid cells (ILC2s) in the skin of mice with IL-33 overexpression in keratinocytes are ...heterogeneous and consist of two distinct populations: skin-resident ILC2s and circulating ILC2s. They show that the circulating subset of skin ILC2s migrates to draining lymph nodes during hapten-induced cutaneous inflammation to potentially enhance the adaptive immune response.
Background Staphylococcus aureus is an opportunistic pathogen that colonizes the skin of patients with atopic dermatitis (AD) and aggravates their disease. Neutrophils and the cytokines IL-17A and ...IL-17F, which drive the expression of the neutrophil-attracting chemokines, are important for the clearance of S aureus infection. The cytokine IL-22 is often coproduced by IL-17-secreting cells. The levels of IL-22 are elevated in AD skin lesions. Objective We sought to determine the role of IL-22 in the clearance of S aureus infection of mouse skin subjected to tape stripping, a surrogate for scratching, a cardinal feature of AD. Methods S aureus was applied to the tape-stripped skin of wild-type and Il22-/- mice. Bacterial burden was evaluated by enumerating colony-forming units. Quantitative PCR and ELISA were performed to quantify Il22 mRNA and IL-22 protein in mouse and human skin. Flow cytometry was used to enumerate neutrophils in the skin. Results Scratching the skin of healthy adults and tape stripping of mouse skin induced local expression of Il22 mRNA and IL-22 protein. Induction of Il22 expression by tape stripping was dependent on IL-23 and gamma delta T cells. Clearance of S aureus from tape-stripped skin was significantly impaired in Il22-/- mice. Neutrophil infiltration and upregulation of expression of genes encoding the antimicrobial peptides antigen-6/urokinase-type plasminogen activator receptor related protein-1 and beta -DEFENSIN 14 and the chemokine (C-X-C motif) ligand following tape stripping were significantly impaired in Il22-/- mice. Conclusions These findings show that IL-22 is important for limiting the growth of S aureus on mechanically injured skin and caution that IL-23 and IL-22 blockade in patients with AD may enhance susceptibility to staphylococcal skin infection.
Display omitted
Skin colonization with Staphylococcus aureus aggravates atopic dermatitis and exaggerates allergic skin inflammation in mice. IL-4 receptor α (IL-4Rα) blockade is beneficial in atopic ...dermatitis and reduces Saureus skin colonization through unknown mechanisms. The cytokine IL-17A restrains Saureus growth.
This study sought to examine the effect of IL-4Rα blockade on Saureus colonization at sites of allergic skin inflammation in mice and determine the mechanism involved.
BALB/c mice were epicutaneously sensitized with ovalbumin (OVA). Immediately after, PSVue 794-labeled S aureus strain SF8300 or saline was applied and a single dose of anti-IL-4Rα blocking antibody, a mixture of anti-IL-4Rα and anti-IL-17A blocking antibodies, or IgG isotype controls were administered intradermally. Saureus load was assessed 2 days later by in vivo imaging and enumeration of colony forming units. Skin cellular infiltration was examined by flow cytometry and gene expression by quantitative PCR and transcriptome analysis.
IL-4Rα blockade decreased allergic skin inflammation in OVA-sensitized skin, as well as in OVA-sensitized and Saureus–exposed skin, evidenced by significantly decreased epidermal thickening and reduced dermal infiltration by eosinophils and mast cells. This was accompanied by increased cutaneous expression of Il17a and IL-17A–driven antimicrobial genes with no change in Il4 and Il13 expression. IL-4Rα blockade significantly decreased Saureus load in OVA-sensitized and S aureus–exposed skin. IL-17A blockade reversed the beneficial effect of IL-4Rα blockade on Saureus clearance and reduced the cutaneous expression of IL-17A–driven antimicrobial genes.
IL-4Rα blockade promotes Saureus clearance from sites of allergic skin inflammation in part by enhancing IL-17A expression.
EC OVA sensitized Il22-/- mice exhibited diminished eosinophil and neutrophil airway infiltration and decreased AHR following i.n. OVA challenge. ...Il22-/- mice exhibited enhanced IFNg, but normal ...IL-13 and IL-17 production in the lungs.
PDF
