The human ortholog MRGPRX2 and the mice ortholog, Mrgprb2 are activated by basic secretagogues and neurokinins. A number of commonly used small-molecule drugs (e.g., neuromuscular blocking agents, fluoroquinolones, vancomycin) have been recently shown to activate these receptors under in vitro experimental conditions, what results in mast cell degranulation. The above drugs are also known to cause IgE-mediated anaphylactic reactions in allergic patients. The new findings on mechanisms of drug-induced mast cell degranulation may modify the current management of drug hypersensitivity reactions. Clinical interpretation of mild drug-provoked hypersensitivity reactions, interpretation of skin test with a drug of interest or further recommendations for patients suspected of drug allergy are likely to be reconsidered. In the paper we discussed future directions in research on identification and differentiation of MRGPRX2-mediated and IgE-dependent mast cell degranulation in patients presenting clinical features of drug-induced hypersensitivity reactions.

A biomarker is a defined characteristic measured as an indicator of normal, biologic, pathogenic processes, or biological responses to an exposure or intervention. Diagnostic biomarkers are used to detect a disease or a subtype of a disease; monitoring biomarkers are measured serially to assess a medical condition; response biomarkers are used to check biologic response following a medical intervention; predictive biomarkers are used to identify patients who are more likely to respond to a medical intervention; and prognostic biomarkers are used to assess the future likelihood of a clinical event. Although biomarkers have been extensively investigated and validated in many diseases and pathologies, very few are currently useful for the diagnosis, evaluation of disease activity, and treatment of hereditary angioedema (HAE). Pathophysiologic pathways involved in HAE reveal a plethora of molecules from the complement, coagulation, and fibrinolysis systems or from the vascular endothelium, which may serve as biomarkers. The most promising candidates, together with their laboratory readout systems, should be evaluated with regard to their analytical and clinical validity and utility. To be highly specific, such biomarkers should be linked to the pathomechanisms of HAE, particularly the bradykinin-generating cascade. Additionally, major advances in high-throughput omics-based technologies may facilitate the discovery of new candidate biomarkers in the future. This review will cover the existing as well as future potential biomarkers that will support the diagnosis, monitor disease activity, and can be used to assess the efficacy of new avenues of therapy of HAE and other forms of angioedema.

Epithelia in the skin, gut and other environmentally exposed organs display a variety of mechanisms to control microbial communities and limit potential pathogenic microbial invasion. Naturally occurring antimicrobial proteins/peptides and their synthetic derivatives (here collectively referred to as AMPs) reinforce the antimicrobial barrier function of epithelial cells. Understanding how these AMPs are functionally regulated may be important for new therapeutic approaches to combat microbial infections. Some AMPs are subject to redox-dependent regulation. This review aims to: (i) explore cysteine-based redox active AMPs in skin and intestine; (ii) discuss casual links between various redox environments of these barrier tissues and the ability of AMPs to control cutaneous and intestinal microbes; (iii) highlight how bacteria, through intrinsic mechanisms, can influence the bactericidal potential of redox-sensitive AMPs.

The members of the ZC3H12/MCPIP/Regnase family of RNases have emerged as important regulators of inflammation. In contrast to Regnase-1, -2 and -4, a thorough characterization of Regnase-3 (Reg-3) has not yet been explored. Here we demonstrate that Reg-3 differs from other family members in terms of NYN/PIN domain features, cellular localization pattern and substrate specificity. Together with Reg-1, the most comprehensively characterized family member, Reg-3 shared IL-6, IER-3 and Reg-1 mRNAs, but not IL-1β mRNA, as substrates. In addition, Reg-3 was found to be the only family member which regulates transcript levels of TNF, a cytokine implicated in chronic inflammatory diseases including psoriasis. Previous meta-analysis of genome-wide association studies revealed Reg-3 to be among new psoriasis susceptibility loci. Here we demonstrate that Reg-3 transcript levels are increased in psoriasis patient skin tissue and in an experimental model of psoriasis, supporting the immunomodulatory role of Reg-3 in psoriasis, possibly through degradation of mRNA for TNF and other factors such as Reg-1. On the other hand, Reg-1 was found to destabilize Reg-3 transcripts, suggesting reciprocal regulation between Reg-3 and Reg-1 in the skin. We found that either Reg-1 or Reg-3 were expressed in human keratinocytes in vitro. However, in contrast to robustly upregulated Reg-1 mRNA levels, Reg-3 expression was not affected in the epidermis of psoriasis patients. Taken together, these data suggest that epidermal levels of Reg-3 are negatively regulated by Reg-1 in psoriasis, and that Reg-1 and Reg-3 are both involved in psoriasis pathophysiology through controlling, at least in part different transcripts.

For the first time we present data showing that metabolic targeted therapy with dichloroacetate (DCA) may improve the outcome of photodynamic therapy. This treatment modality can be easily introduced into clinical practice guidelines.

Chemerin is a chemoattractant protein with adipokine properties encoded by the retinoic acid receptor responder 2 (RARRES2) gene. It has gained more attention in the past few years due to its multilevel impact on metabolism and immune responses. However, mechanisms controlling the constitutive and regulated expression of RARRES2 in a variety of cell types remain obscure. To our knowledge, this report is the first to show that DNA methylation plays an important role in the cell-specific expression of RARRES2 in adipocytes, hepatocytes, and B lymphocytes. Using luciferase reporter assays, we determined the proximal fragment of the RARRES2 gene promoter, located from − 252 to + 258 bp, to be a key regulator of transcription. Moreover, we showed that chemerin expression is regulated in murine adipocytes by acute-phase cytokines, interleukin 1β and oncostatin M. In contrast with adipocytes, these cytokines exerted a weak, if any, response in mouse hepatocytes, suggesting that the effects of IL-1β and OSM on chemerin expression is specific to fat tissue. Together, our findings highlight previously uncharacterized mediators and mechanisms that control chemerin expression.