Perinatal androgens organize sex differences in mast cells and attenuate anaphylaxis severity into adulthood

Mackey, Emily; Thelen, Kyan; Bali, Vedrana; Fardisi, Mahsa; Trowbridge, Madalyn; Jordan, Cynthia L.; Moeser, Adam J.

doi:10.1073/pnas.1915075117

Cited by 32 publications

(32 citation statements)

References 57 publications

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“…Mast cells (MCs) serving as a cellular link among numerous components (FcγRIII, IL-1, PKC/NF-κB) in inflammatory arthritis increase both in RA patients and in animal models [ 85 ]. The fact that mast cell-associated diseases, including allergy/anaphylaxis and neuroinflammatory pain disorders, exhibit a gender bias towards women could also explain the high prevalence of RA in females [ 86 ].…”

Section: Zinc and Cadmium In The Aetiology And As Risk Factors Of mentioning

confidence: 99%

Zinc and Cadmium in the Aetiology and Pathogenesis of Osteoarthritis and Rheumatoid Arthritis

Frangos

Maret

2020

Nutrients

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Osteoarthritis (OA) and rheumatoid arthritis (RA) are inflammatory articular conditions with different aetiology, but both result in joint damage. The nutritionally essential metal zinc (Zn2+) and the non-essential metal cadmium (Cd2+) have roles in these arthritic diseases as effectors of the immune system, inflammation, and metabolism. Despite both metal ions being redox-inert in biology, they affect the redox balance. It has been known for decades that zinc decreases in the blood of RA patients. It is largely unknown, however, whether this change is only a manifestation of an acute phase response in inflammation or relates to altered availability of zinc in tissues and consequently requires changes of zinc in the diet. As a cofactor in over 3000 human proteins and as a signaling ion, zinc affects many pathways relevant for arthritic disease. How it affects the diseases is not just a question of zinc status, but also an issue of mutations in the many proteins that maintain cellular zinc homoeostasis, such as zinc transporters of the ZIP (Zrt-/Irt-like protein) and ZnT families and metallothioneins, and the multiple pathways that change the expression of these proteins. Cadmium interferes with zinc’s functions and there is increased uptake under zinc deficiency. Remarkably, cadmium exposure through inhalation is now recognized in the activation of macrophages to a pro-inflammatory state and suggested as a trigger of a specific form of nodular RA. Here, we discuss how these metal ions participate in the genetic, metabolic, and environmental factors that lead to joint destruction. We conclude that both metal ions should be monitored routinely in arthritic disease and that there is untapped potential for prognosis and treatment.

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Section: Zinc and Cadmium In The Aetiology And As Risk Factors Of mentioning

confidence: 99%

Zinc and Cadmium in the Aetiology and Pathogenesis of Osteoarthritis and Rheumatoid Arthritis

Frangos

Maret

2020

Nutrients

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“…Histamine contents in BMMCs derived from female C57BL/6J mice were found to be higher than those from male mice [90]. Histamine contents in BMMCs were significantly decreased when they were prepared from the adult female mice exposed to androgen at their perinatal stages.…”

Section: Histamine-mediated Granule Maturation Of Mast Cellsmentioning

confidence: 83%

Roles of IgE and Histamine in Mast Cell Maturation

Tanaka

Furuta

2021

Cells

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Mast cells are activated upon immunoglobulin E (IgE)-mediated antigen stimulation, and release a wide variety of mediators, including histamine to trigger inflammatory responses. The surface expression levels of Fce receptor I (FceRI), a high affinity receptor of IgE, were found to be positively regulated by IgE. IgE could protect murine cultured mast cells from apoptotic cell death induced by the deprivation of interleukin-3 and a certain kind of IgE could activate immature mast cells in the absence of antigens, leading to the release of pro-inflammatory cytokines and a transient increase in histamine synthesis. Histamine synthesis in mast cells was found to be required for the maturation of murine connective tissue-type mast cells, raising the possibility that IgE indirectly modulates local mast cell maturation. Although it remains controversial to what extent this concept of “monomeric IgE effects” could have relevance in the modulation of human mast cell functions, the therapeutic effects of anti-IgE antibodies might be accounted for in terms of the decreased serum IgE concentrations. Because drastic increases in serum IgE concentrations are often observed in patients with atopic dermatitis and chronic urticaria, a close investigation of the roles of IgE in mast cell maturation should contribute to development of novel therapeutic approaches for these inflammatory diseases.

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“…Automated western blot was performed according to the manufacturer's protocol (Protein Simple, San Jose, CA, USA; https://www.proteinsimple.com/wes.html [36,37]). Briefly, the proteins were extracted with lysis buffer (150 m m NaCl, 100 m m Tris/HCl pH 8, 1% NP‐40, and protease inhibitors) and the protein concentration was adjusted to 0.5–1 μg·μL −1 .…”

Section: Methodsmentioning

confidence: 99%

Regulation of MRE11A by UBQLN4 leads to cisplatin resistance in patients with esophageal squamous cell carcinoma

et al. 2021

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Resistance to standard cisplatin‐based chemotherapies leads to worse survival outcomes for patients with esophageal squamous cell carcinoma (ESCC). Therefore, there is an urgent need to understand the aberrant mechanisms driving resistance in ESCC tumors. We hypothesized that ubiquilin‐4 (UBQLN4), a protein that targets ubiquitinated proteins to the proteasome, regulates the expression of Meiotic Recombination 11 Homolog A (MRE11A), a critical component of the MRN complex and DNA damage repair pathways. Initially, immunohistochemistry analysis was conducted in specimens from patients with ESCC (n = 120). In endoscopic core ESCC biopsies taken from 61 patients who underwent neoadjuvant chemotherapy (NAC) (5‐fluorouracil and cisplatin), low MRE11A and high UBQLN4 protein levels were associated with reduced pathological response to NAC (P < 0.001 and P < 0.001, respectively). Multivariable analysis of surgically resected ESCC tissues from 59 patients revealed low MRE11A and high UBLQN4 expression as independent factors that can predict shorter overall survival [P = 0.01, hazard ratio (HR) = 5.11, 95% confidence interval (CI), 1.45–18.03; P = 0.02, HR = 3.74, 95% CI, 1.19–11.76, respectively]. Suppression of MRE11A expression was associated with cisplatin resistance in ESCC cell lines. Additionally, MRE11A was found to be ubiquitinated after cisplatin treatment. We observed an amplification of UBQLN4 gene copy numbers and an increase in UBQLN4 protein levels in ESCC tissues. Binding of UBQLN4 to ubiquitinated‐MRE11A increased MRE11A degradation, thereby regulating MRE11A protein levels following DNA damage and promoting cisplatin resistance. In summary, MRE11A and UBQLN4 protein levels can serve as predictors for NAC response and as prognostic markers in ESCC patients.

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Perinatal androgens organize sex differences in mast cells and attenuate anaphylaxis severity into adulthood

Cited by 32 publications

References 57 publications

Zinc and Cadmium in the Aetiology and Pathogenesis of Osteoarthritis and Rheumatoid Arthritis

Zinc and Cadmium in the Aetiology and Pathogenesis of Osteoarthritis and Rheumatoid Arthritis

Roles of IgE and Histamine in Mast Cell Maturation

Regulation of MRE11A by UBQLN4 leads to cisplatin resistance in patients with esophageal squamous cell carcinoma

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