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Factor XIII-A in Diseases: Role Beyond Blood Coagulation

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Factor XIII-A in Diseases: Role Beyond Blood Coagulation International Journal of Molecular Sciences Review Factor XIII-A in Diseases: Role Beyond Blood Coagulation Katalin Dull, Fruzsina Fazekas and Dániel Tör˝ocsik* Department of Dermatology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H4032 Debrecen, Hungary; [email protected] (K.D.); [email protected] (F.F.) * Correspondence: [email protected]; Tel.: +36-52-255-602 Abstract: Multidisciplinary research from the last few decades has revealed that Factor XIII subunit A (FXIII-A) is not only involved in blood coagulation, but may have roles in various diseases. Here, we aim to summarize data from studies involving patients with mutations in the F13A1 gene, performed in FXIII-A knock-out mice models, clinical and histological studies assessing correlations between diseases severity and FXIII-A levels, as well as from in vitro experiments. By providing a complex overview on its possible role in wound healing, chronic inflammatory bowel diseases, athe-rosclerosis, rheumatoid arthritis, chronic inflammatory lung diseases, chronic rhinosinusitis, solid tumors, hematological malignancies, and obesity, we also demonstrate how the field evolved from using FXIII-A as a marker to accept and understand its active role in inflammatory and malignant diseases. Keywords: Factor XIII subunit A; chronic inflammatory diseases; malignancies 1. Introduction In the plasma, Factor XIII is present as a heterotetramer (FXIII-A2B2), consisting of two A subunits (FXIII-A) with catalytic activity and two B subunits (FXIII-B) that inhibit FXIII- A by binding to it. During the coagulation cascade, thrombin cleaves off the activation peptide from A subunit, the B subunit dissociates in a Ca2+-dependent manner, and FXIII-A Citation: Dull, K.; Fazekas, F.; becomes an active transglutaminase cross-linking fibrin strands, accounting for its role in Tör˝ocsik,D. Factor XIII-A in Diseases: stabilizing fibrin clots in the final stage of blood coagulation (reviewed in [1–4]). Role Beyond Blood Coagulation. Int. Immunohistochemical detection later revealed that FXIII-A is also found intracel- J. Mol. Sci. 2021, 22, 1459. https:// lularly (cFXIII-A) in various cell types, where it may be activated without proteolytic doi.org/10.3390/ijms22031459 cleavage by increased intracellular Ca2+ concentrations [5,6]. In the early embryonic life, mesenchymal histiocytes and hepatocytes [7] stained positive for FXIII-A; in adult Received: 30 December 2020 life, megakaryocytes [8], platelets [9], monocytes [10,11], macrophages [10,12], dendritic Accepted: 28 January 2021 cells [13], chondrocytes [14–16], osteoblasts [17], preadipocytes [18], corneal keratocytes [19], Published: 1 February 2021 keratinocytes [20], fibroblasts [21], and sebocytes [22] all did as well. Importantly, detection of FXIII-A is still routinely used as a marker in the histological diagnosis of a wide range Publisher’s Note: MDPI stays neutral of inflammatory and malignant skin diseases (reviewed in [23]). Although some of the with regard to jurisdictional claims in reported positive stainings were later found to be dependent on the applied antibody [22], published maps and institutional affil- while with the improvement of functional assays to distinguish macrophages from den- iations. dritic cells, FXIII-A became accepted as a marker of alternatively activated macrophages (a subset which is important in tissue remodeling and not in the elimination of bacteria [24]), rather than of dendritic cells [25–27]. These findings raised intriguing question on the possible role for FXIII-A both intracellularly and in (patho)physiological conditions beyond Copyright: © 2021 by the authors. blood coagulation. Licensee MDPI, Basel, Switzerland. Factor XIII-A deficiency is mainly caused by mutations in the FXIII-A gene (95% This article is an open access article of cases) [28]; while homozygous mutations usually result in symptoms related to an distributed under the terms and impaired blood coagulation, patients with heterozygous mutations are often asymptomatic. conditions of the Creative Commons Identification of patients with decreased or even diminished activity of FXIII-A and patients Attribution (CC BY) license (https:// with genetic variations (SNPs) in the gene F13A1 [29], as well as the generation of genetically creativecommons.org/licenses/by/ modified mouse models [30,31], has led the field into the era of proof-of-concept studies. 4.0/). Int. J. Mol. Sci. 2021, 22, 1459. https://doi.org/10.3390/ijms22031459 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 15 Identification of patients with decreased or even diminished activity of FXIII-A and pa- tients with genetic variations (SNPs) in the gene F13A1 [29], as well as the generation of Int. J. Mol. Sci. 2021, 22, 1459 2 of 14 genetically modified mouse models [30,31], has led the field into the era of proof-of-con- cept studies. Their characterization has demonstrated that indeed FXIII-A is not only in- volved in blood coagulation, but may have a role in wound healing and in basic immuno- logical functionsTheir as well. characterization has demonstrated that indeed FXIII-A is not only involved in blood Implicatingcoagulation, state-of-the but art, may unbiased havea research role in wound strategies healing and molecular and in basic methods immunological into functions FXIII-A researchas well.brought another breakthrough and opened new vistas to define its rela- tionship to diseases,Implicating many of which state-of-the were not art, raised unbiased previously research even strategies at the level and of molecularspec- methods ulation. Wholeinto gene FXIII-A expression research profiling brought has anotherrevealed breakthrough that in alternatively and opened activated new mac- vistas to define its rophages, cFXIII-Arelationship may alter to the diseases, expression many of of genes which related were to not immune raised previouslyfunctions and even to at the level of wound responsespeculation. [32]; it has Wholealso shown gene that expression FXIII-A profiling shows abundant has revealed expression that in alternativelylevels in activated adipose tissue,macrophages, with a suggested cFXIII-A role in may adip alterose tissue the expression development of genes [33]. related Protein to detection immune functions and confirmed its possibleto wound intracellular response [32 substrate]; it has also in shownthe pathogenesis that FXIII-A of shows atherosclerosis abundant expression[34]. levels in Modern “geneadipose hunting”, tissue, using with whole a suggested exome role sequencing, in adipose has tissue identified development mutations [33]. Proteinin detection confirmed its possible intracellular substrate in the pathogenesis of atherosclerosis [34]. FXIII-A to be the cause of familial dermatofibromas [35]. In addition, clinical studies have Modern “gene hunting”, using whole exome sequencing, has identified mutations in found and explained correlations with its altered expression levels and disease pathogen- FXIII-A to be the cause of familial dermatofibromas [35]. In addition, clinical studies esis/severity in inflammatory diseases [36–42]. have found and explained correlations with its altered expression levels and disease In this review, we aim to summarize the available results and our recent understand- pathogenesis/severity in inflammatory diseases [36–42]. ing on the role of FXIII-A in various diseases (Figure 1). In this review, we aim to summarize the available results and our recent understanding on the role of FXIII-A in various diseases (Figure1). 2. FXIII-A in Diseases Figure 1. Summary overview of diseases discussed in this review in which FXIII-A may play a role. Created with Figure 1. Summary overview of diseases discussed in this review in which FXIII-A may play a BioRender.com. role. Created with BioRender.com. 2. FXIII-A in Diseases 2.1. FXIII-A in 2.1.Wound FXIII-A Healing in Wound Healing Patients diagnosedPatients with diagnosed FXIII-A deficiency with FXIII-A often deficiency show impa oftenired show tissue impaired repair [43,44]. tissue repair [43,44]. This phenomenonThis was phenomenon characterized was by characterized Inbal et al. in by a transgenic Inbal et al. mice in a model transgenic with a mice tar- model with a geted deletiontargeted of exon deletion7 in the F13A1 of exon gene, 7 in where the F13A1 delayedgene, re-epithelialization where delayed re-epithelialization and ne- and crotized fissuresnecrotized were detected fissures [45]. were Importantly, detected [45 when]. Importantly, deficient whenmice were deficient treated mice with were treated with recombinant FXIII-A,recombinant wound FXIII-A, healing wound was norm healingal, suggesting was normal, a pivotal suggesting role for a pivotal FXIII-A role for FXIII-A from the plasma/extracellularfrom the plasma/extracellular space. The workgroup space. hypothesized The workgroup that hypothesizedFXIII-A may have that FXIII-A may a regulatory rolehave in multiple a regulatory aspects role of in wound multiple healing: aspects stabilize of wound fibrin healing: clots and stabilize extracel- fibrin clots and lular matrix, modulateextracellular monocy matrix,te functions, modulate monocytepromote angiog functions,enesis, promote and upregulate angiogenesis, pro- and upregulate angiogenic earlyproangiogenic growth response early transcription growth response factor transcription 1 (Egr-1). factor 1 (Egr-1). Angiogenesis andAngiogenesis neovascularization and neovascularization also have a central also have role ain central
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