Innate Immune Dysfunction in Rosacea Promotes Photosensitivity and Vascular Adhesion Molecule Expression

Kulkarni, Nikhil Nitin; Takahashi, Toshiya; Sanford, James A.; Tong, Yun; Gombart, Adrian F.; Hinds, Brian; Cheng, James; Gallo, Richard L.

doi:10.1016/j.jid.2019.08.436

Cited by 43 publications

(42 citation statements)

References 41 publications

(45 reference statements)

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“…Mast cell activation by LL-37 is thought to act through the MrgX2 receptor, a G protein-coupled receptor (GPCR), but other receptors, including FPRL1 and P2X7, have been proposed (88). The proinflammatory functions of cathelicidin have been observed in many human diseases and mouse inflammatory models (51,(89)(90)(91)(92), and this capacity to enhance tissue inflammation is consistent with the observations in our study. Interestingly, in the absence of cathelicidin, we saw an enhancement of neutrophil MPO release (Fig.…”

Section: Discussionsupporting

confidence: 91%

Host Cathelicidin Exacerbates Group BStreptococcusUrinary Tract Infection

Patras

Coady

Babu

et al. 2020

mSphere

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Group B Streptococcus (GBS) causes frequent urinary tract infection (UTI) in susceptible populations, including individuals with type 2 diabetes and pregnant women; however, specific host factors responsible for increased GBS susceptibility in these populations are not well characterized. Here, we investigate cathelicidin, a cationic antimicrobial peptide, known to be critical for defense during UTI with uropathogenic Escherichia coli (UPEC). We observed a loss of antimicrobial activity of human and mouse cathelicidins against GBS and UPEC in synthetic urine and no evidence for increased cathelicidin resistance in GBS urinary isolates. Furthermore, we found that GBS degrades cathelicidin in a protease-dependent manner. Surprisingly, in a UTI model, cathelicidin-deficient (Camp−/−) mice showed decreased GBS burdens and mast cell recruitment in the bladder compared to levels in wild-type (WT) mice. Pharmacologic inhibition of mast cells reduced GBS burdens and histamine release in WT but not Camp−/− mice. Streptozotocin-induced diabetic mice had increased bladder cathelicidin production and mast cell recruitment at 24 h postinfection with GBS compared to levels in nondiabetic controls. We propose that cathelicidin is an important immune regulator but ineffective antimicrobial peptide against GBS in urine. Combined, our findings may in part explain the increased frequency of GBS UTI in diabetic and pregnant individuals. IMPORTANCE Certain populations such as diabetic individuals are at increased risk for developing urinary tract infections (UTI), although the underlying reasons for this susceptibility are not fully known. Additionally, diabetics are more likely to become infected with certain types of bacteria, such as group B Streptococcus (GBS). In this study, we find that an antimicrobial peptide called cathelicidin, which is thought to protect the bladder from infection, is ineffective in controlling GBS and alters the type of immune cells that migrate to the bladder during infection. Using a mouse model of diabetes, we observe that diabetic mice are more susceptible to GBS infection even though they also have more infiltrating immune cells and increased production of cathelicidin. Taken together, our findings identify this antimicrobial peptide as a potential contributor to increased susceptibility of diabetic individuals to GBS UTI.

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Section: Discussionsupporting

confidence: 91%

Host Cathelicidin Exacerbates Group BStreptococcusUrinary Tract Infection

Patras

Coady

Babu

et al. 2020

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“…The pathogenesis of rosacea is not well understood. Immune dysfunction [87], Demodex [88], ultraviolet radiation exposure [89], and vascular hyperreactivity [90] may all play a role in the pathogenesis of rosacea. The pathogenesis and related mechanisms need further exploration to develop more etiological treatment modalities.…”

Section: Discussionmentioning

confidence: 99%

Rosacea Treatment: Review and Update

Zhang

Tang

Wang

et al. 2020

Dermatol Ther (Heidelb)

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Rosacea is a chronic and inflammatory skin disease characterized by flushing, nontransient erythema, papules/pustules, telangiectasia, and phymatous changes. Secondary manifestations, such as itching, burning, or stinging, are often observed in patients with rosacea. In 2017, a phenotype-based approach for diagnosis and classification was recommended. With the update of the diagnosis and classification of rosacea, treatment options for patients with rosacea have attracted the attention of dermatologists. Here, we summarize the latest advances in rosacea treatment, including skin care and cosmetic treatments, topical therapies, oral therapies, laser- and light-based therapies, injection therapies, treatments for specific types of rosacea, treatments for systemic comorbidities, and combination therapies. The impact of the phenotype-based approach on rosacea treatment and future directions are also discussed.

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“…Rosacea is currently considered by most authors as a disease of the immune system, an inflammatory process including innate and then adaptive immune responses, which gets out of control resulting in vascular, inflammatory, and hypertrophic symptoms [2,5,[14][15][16][17][18][19][20][21][22]. Genetic (46%) and environmental (54%) influences have recently been demonstrated in a study on twins [23], and many associated co-morbidities have been highlighted [24].…”

Section: Rosacea: An Inflammatory Continuummentioning

confidence: 99%

The Pathogenic Role of Demodex Mites in Rosacea: A Potential Therapeutic Target Already in Erythematotelangiectatic Rosacea?

Forton¹

2020

Dermatol Ther (Heidelb)

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Rosacea is an inflammatory continuum, with all characteristics being already present from the onset of the disease, even if not clinically visible. Demodex proliferation also appears to be a continuum process in rosacea, and high Demodex density is beginning to be accepted as an important trigger of the inflammatory cascade and as a marker of rosacea: moreover, papulopustules of rosacea can be treated using acaricides. Immunological studies are providing new hypotheses according to which Demodex may induce tolerogenic dendritic cells and collaborate with VEGF to induce T cell exhaustion favoring its own proliferation. This proliferation may not be clinically visible initially. The interactions among VEGF, Demodex, and immunity need to be explored, and the nosology of rosacea definitions adapted accordingly. The effectiveness of treating any patient who only has visible vascular symptoms with an acaricidal cream needs to be confirmed in prospective controlled clinical trials with long-term follow-up, but it is already important to detect patients with pityriasis folliculorum among those with only vascular symptoms of rosacea in order to treat at least these patients with an acaricidal cream. DIGITAL FEATURES This article is published with digital features to facilitate understanding of the article. You can access the digital features on the article's associated Figshare page. To view digital features for this article go to

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Innate Immune Dysfunction in Rosacea Promotes Photosensitivity and Vascular Adhesion Molecule Expression

Cited by 43 publications

References 41 publications

Host Cathelicidin Exacerbates Group BStreptococcusUrinary Tract Infection

Host Cathelicidin Exacerbates Group BStreptococcusUrinary Tract Infection

Rosacea Treatment: Review and Update

The Pathogenic Role of Demodex Mites in Rosacea: A Potential Therapeutic Target Already in Erythematotelangiectatic Rosacea?

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