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Advances in Experimental and Clinical Aspects of Allergies and Autoimmunity

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: 20 February 2025 | Viewed by 4647

Special Issue Editors

Prof. Dr. Krzysztof Bryniarski

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Guest Editor
Department of Immunology, Jagiellonian University Medical College, 18 Czysta St., 31-121 Krakow, Poland
Interests: contact and delayed-type hypersensitivity; exosomes; extracellular vesicles; immune regulation; immune tolerance; mechanisms underlying hypersensitivity reactions; miRNAs; mouse models of allergy and autoimmunity
Special Issues, Collections and Topics in MDPI journals
Dr. Katarzyna Nazimek

E-Mail Website
Guest Editor
Department of Immunology, Jagiellonian University Medical College, 18 Czysta St., 31-121 Krakow, Poland
Interests: contact and delayed-type hypersensitivity; exosomes; extracellular vesicles; immune regulation via miRNAs; immune tolerance; macrophages; mechanisms underlying hypersensitivity reactions; mouse models of allergy and autoimmunity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to introduce to you the new Special Issue of the Molecular Immunology Section of the International Journal of Molecular Sciences focused on “Advances in Experimental and Clinical Aspects of Allergies and Autoimmunity”.

Rising rates of allergies and autoimmunity issues have prompted researchers and clinicians to search for novel, efficient and personalized treatment strategies. This requires a better understanding of the immune mechanisms underlying allergic and autoimmune reactions, the investigation of possible methods of regulating/modulating these processes and uncovering the causes behind the increasing incidence of these diseases.

Extracellular vesicles (EVs), miRNAs and long noncoding RNAs (lncRNAs) receive special attention due to their involvement in systemic intercellular communication, including physiological and pathological immune-related conditions. Recent advances in understanding complex biological functions of EVs, miRNAs and lncRNAs have shown them to be promising candidates for creating novel pathways in specific immunotherapies, firstly, by complimenting existing treatments in reducing toxic side effects and increasing the specificity, and, secondly, by altering unwanted immune responses underlying allergic or autoimmune disorders. Furthermore, a growing body of evidence supports the introduction of monoclonal antibody-based therapeutics into routine clinical practice. Moreover, our knowledge of desensitization-induced immune tolerance/regulatory mechanisms is also currently increasing.

Therefore, this Special Issue aims to present the current advances in our understanding of all, experimental and clinical, aspects of allergies and autoimmunity. We gladly accept articles describing newly discovered mechanisms of immune tolerance induction and uncovering the immunotherapeutic potential of EVs, miRNAs, lncRNAs and biologics in allergies and autoimmunity.

We cordially invite all interested researchers to submit original and review articles covering relevant, basic research and clinical findings so that the Special Issue entitled “Advances in Experimental and Clinical Aspects of Allergies and Autoimmunity: Mechanisms, Therapies and Beyond” can become a platform for sharing experiences between researchers and clinicians.

Please accept our sincerest thanks in advance for participating in this publishing opportunity.

Prof. Dr. Krzysztof Bryniarski
Dr. Katarzyna Nazimek
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • advanced diagnostics
  • extracellular vesicles
  • hypersensitivity
  • immune regulation
  • long noncoding RNA
  • miRNA
  • novel therapeutics
  • research models of allergy and autoimmunity

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Research

Jump to: Review

19 pages, 1609 KiB  
Article
Sialic-Acid-Related Enzymes of B Cells and Monocytes as Novel Markers to Discriminate Improvement Categories and to Fulfill Two Remission Definitions in Rheumatoid Arthritis
by Lieh-Bang Liou, Ping-Han Tsai, Yao-Fan Fang, Yen-Fu Chen, Chih-Chieh Chen and Jenn-Haung Lai
Int. J. Mol. Sci. 2023, 24(16), 12998; https://doi.org/10.3390/ijms241612998 - 20 Aug 2023
Cited by 1 | Viewed by 1325
Abstract
The enzymes α-2,6-sialyltransferase 1 (ST6Gal1), neuraminidase 1 (Neu1), α-2,3-sialyltransferase 1 (ST3Gal1), and neuraminidase 3 (Neu3) are known to affect immune cell function. However, it is not known whether the levels of these enzymes relate to remission definitions or differentiate American College of Rheumatology [...] Read more.
The enzymes α-2,6-sialyltransferase 1 (ST6Gal1), neuraminidase 1 (Neu1), α-2,3-sialyltransferase 1 (ST3Gal1), and neuraminidase 3 (Neu3) are known to affect immune cell function. However, it is not known whether the levels of these enzymes relate to remission definitions or differentiate American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), and Simplified Disease Activity Index (SDAI) responses in patients with rheumatoid arthritis (RA). We measured the ST6Gal1, Neu1, ST3Gal1, and Neu3 levels of B cells and monocytes in RA patients and correlated the cells’ enzyme levels/ratios with the improvement in the ACR, EULAR and SDAI responses and with the two remission definitions. The difference in the B-cell Neu1 levels differed between the ACR 70% improvement and non-improvement groups (p = 0.043), between the EULAR good major response (improvement) and non-good response groups (p = 0.014), and also between the SDAI 50% or 70% improvement and non-improvement groups (p = 0.001 and 0.018, respectively). The same held true when the RA patients were classified by positive rheumatoid factor or the use of biologics. The B-cell Neu1 levels significantly indicated 2005 modified American Rheumatism Association and 2011 ACR/EULAR remission definitions (area under the curve (AUC) = 0.674 with p = 0.001, and AUC = 0.682 with p < 0.001, respectively) in contrast to the CRP and ESR (all AUCs < 0.420). We suggest that B-cell Neu1 is superior for discriminating ACR, EULAR, and SDAI improvement and is good for predicting two kinds of remission definitions. Full article
(This article belongs to the Special Issue Advances in Experimental and Clinical Aspects of Allergies and Autoimmunity)
►▼ Show Figures

Figure 1

Figure 1
<p>Comparisons of the difference of monocyte and B-cell enzyme levels/ratios between various ACR improvements and their non-improvements. (<b>A</b>) The B-cell Neu1 difference (M0 − M3) fulfilled the ACR 70% improvement criteria (<span class="html-italic">n</span> = 23), compared with those not fulfilled (<span class="html-italic">n</span> = 67), <span class="html-italic">p</span> = 0.043. (<b>B</b>) The monocyte Neu3 difference (M0 − M12) fulfilled the ACR 20% improvement criteria (<span class="html-italic">n</span> = 65), compared with those not fulfilled (<span class="html-italic">n</span> = 6), <span class="html-italic">p</span> = 0.037. (<b>C</b>) The B-cell ST6 difference (M0 − M12) fulfilled the ACR 20% improvement criteria (<span class="html-italic">n</span> = 62), compared with those not fulfilled (<span class="html-italic">n</span> = 5), <span class="html-italic">p</span> = 0.050. (<b>D</b>) The monocyte ST3/Neu3 ratio difference (M0 − M12) fulfilled the ACR 70% improvement criteria (<span class="html-italic">n</span> = 26), compared with those not fulfilled (<span class="html-italic">n</span> = 38), <span class="html-italic">p</span> = 0.042. All comparisons were analysed using the Mann–Whitney U test.</p> Full article ">Figure 2
<p>Comparisons of the difference of monocyte and B-cell enzyme levels/ratios between various ACR improvements and their non-improvements in RA patients with positive rheumatoid factor. (<b>A</b>) The B-cell Neu1 difference (M0 − M3) fulfilled the ACR 70% improvement criteria (<span class="html-italic">n</span> = 21), compared with those not fulfilled (<span class="html-italic">n</span> = 53), <span class="html-italic">p</span> = 0.041. (<b>B</b>) The B-cell ST6 difference (M0 − M3) fulfilled the ACR 70% improvement criteria (<span class="html-italic">n</span> = 21), compared with those not fulfilled (<span class="html-italic">n</span> = 50), <span class="html-italic">p</span> = 0.022; that of the B-cell ST6 difference yielded <span class="html-italic">p</span> = 0.024 (ACR 50%, M0 − M12). (<b>C</b>) The monocyte Neu3 difference (M0 − M12) fulfilled the ACR 20% improvement criteria (<span class="html-italic">n</span> = 67), compared with those not fulfilled (<span class="html-italic">n</span> = 8), <span class="html-italic">p</span> = 0.029; that of the monocyte ST6/Neu1 ratio difference rendered <span class="html-italic">p</span> = 0.007 (ACR 70%, M0 − M12); that of the monocyte ST6 difference yielded <span class="html-italic">p</span> = 0.019 (ACR 50%, M0 − M15). (<b>D</b>) The B-cell ST3 difference (M0 − M3) fulfilled the ACR 70% improvement criteria (<span class="html-italic">n</span> = 21), compared with those not fulfilled (<span class="html-italic">n</span> = 49), <span class="html-italic">p</span> = 0.013; that of the B-cell ST3 difference provided <span class="html-italic">p</span> = 0.046 (ACR 50%, M0 − M12); that of the B-cell Neu 3 difference yielded <span class="html-italic">p</span> = 0.015 (ACR 70%, M0 − M3). All comparisons were analysed using the Mann–Whitney U test.</p> Full article ">Figure 3
<p>Comparisons of the difference of monocyte and B-cell enzyme levels/ratios between various ACR improvements and their non-improvements in RA patients with positive anti-CCP antibodies. (<b>A</b>) The B-cell ST6 difference (M0 − M12) fulfilled the ACR 70% improvement (<span class="html-italic">n</span> = 75) criteria, compared with those not fulfilled (<span class="html-italic">n</span> = 6), <span class="html-italic">p</span> = 0.030. (<b>B</b>) The monocyte ST6 difference gave <span class="html-italic">p</span> = 0.039 for ACR 70% improvement (<span class="html-italic">n</span> = 50) vs. non-improvement (<span class="html-italic">n</span> = 31) (M0 − M15). (<b>C</b>) The monocyte ST3/Neu3 ratio difference rendered <span class="html-italic">p</span> = 0.036 for ACR 70% improvement (<span class="html-italic">n</span> = 33) vs. non-improvement (<span class="html-italic">n</span> = 41) (M0 − M12). All comparisons were analysed using the Mann–Whitney U test.</p> Full article ">Figure 4
<p>Comparisons of the difference of monocyte and B-cell enzyme levels/ratios between various ACR improvements and their non-improvements in RA patients with use of biologics. (<b>A</b>) The B-cell Neu1 difference (M0 − M3) fulfilled the ACR 50% improvement criteria (<span class="html-italic">n</span> = 26), compared with those not fulfilled (<span class="html-italic">n</span> = 16), <span class="html-italic">p</span> = 0.029. (<b>B</b>) The B-cell ST6/Neu1 ratio difference (M0 − M3) fulfilled the ACR 50% improvement (<span class="html-italic">n</span> = 21), compared with those not fulfilled (<span class="html-italic">n</span> = 15) gave <span class="html-italic">p</span> = 0.037. (<b>C</b>) The monocyte ST6/Neu1 ratio difference (M0 − M3) fulfilled the ACR 20% improvement (<span class="html-italic">n</span> = 31), compared with those not fulfilled (<span class="html-italic">n</span> = 6), <span class="html-italic">p</span> = 0.009. (<b>D</b>) The monocyte ST3/Neu3 ratio difference (M0 − M12) fulfilled the ACR 70% improvement (<span class="html-italic">n</span> = 10), compared with those not fulfilled (<span class="html-italic">n</span> = 27), <span class="html-italic">p</span> = 0.028. All comparisons were analysed using the Mann–Whitney U test.</p> Full article ">Figure 5
<p>Comparison of the B-cell Neu1 level and DAS28 scores between baseline and later months. The B-cell Neu1 level was significantly lower in (<b>A</b>) month 12 (<span class="html-italic">n</span> = 72) and (<b>B</b>) month 15 (<span class="html-italic">n</span> = 48) than month 0 (<span class="html-italic">n</span> = 100) (<span class="html-italic">p</span> = 0.009 and &lt;0.001, respectively). DAS28-ESR scores were significantly lower in (<b>C</b>) month 12 and (<b>D</b>) month 15 than month 0 (<span class="html-italic">p</span> &lt; 0.001 and &lt;0.001, respectively). DAS28-MCP-1 scores were significantly lower in (<b>E</b>) month 12 and (<b>F</b>) month 15 than month 0 (<span class="html-italic">p</span> &lt; 0.001 and &lt;0.001, respectively). All comparisons were analysed using the Mann–Whitney U test.</p> Full article ">
16 pages, 5446 KiB  
Article
PPARδ Agonist GW501516 Suppresses the TGF-β-Induced Profibrotic Response of Human Bronchial Fibroblasts from Asthmatic Patients
by Milena Paw, Dawid Wnuk, Zbigniew Madeja and Marta Michalik
Int. J. Mol. Sci. 2023, 24(9), 7721; https://doi.org/10.3390/ijms24097721 - 23 Apr 2023
Cited by 2 | Viewed by 1858
Abstract
The airway wall remodeling observed in asthma is associated with subepithelial fibrosis and enhanced activation of human bronchial fibroblasts (HBFs) in the fibroblast to myofibroblast transition (FMT), induced mainly by transforming growth factor-β (TGF-β). The relationships between asthma severity, obesity, and hyperlipidemia suggest [...] Read more.
The airway wall remodeling observed in asthma is associated with subepithelial fibrosis and enhanced activation of human bronchial fibroblasts (HBFs) in the fibroblast to myofibroblast transition (FMT), induced mainly by transforming growth factor-β (TGF-β). The relationships between asthma severity, obesity, and hyperlipidemia suggest the involvement of peroxisome proliferator-activated receptors (PPARs) in the remodeling of asthmatic bronchi. In this study, we investigated the effect of PPARδ ligands (GW501516 as an agonist, and GSK0660 as an antagonist) on the FMT potential of HBFs derived from asthmatic patients cultured in vitro. This report shows, for the first time, the inhibitory effect of a PPARδ agonist on the number of myofibroblasts and the expression of myofibroblast-related markers—α-smooth muscle actin, collagen 1, tenascin C, and connexin 43—in asthma-related TGF-β-treated HBF populations. We suggest that actin cytoskeleton reorganization and Smad2 transcriptional activity altered by GW501516 lead to the attenuation of the FMT in HBF populations derived from asthmatics. In conclusion, our data demonstrate that a PPARδ agonist stimulates antifibrotic effects in an in vitro model of bronchial subepithelial fibrosis. This suggests its potential role in the development of a possible novel therapeutic approach for the treatment of subepithelial fibrosis during asthma. Full article
(This article belongs to the Special Issue Advances in Experimental and Clinical Aspects of Allergies and Autoimmunity)
►▼ Show Figures

Figure 1

Figure 1
<p>The PPARδ agonist GW501516 and antagonist GSK0660 administered alone or in combination to HBF cultures had a negligible effect on cell viability and proliferation. HBF populations (<span class="html-italic">n</span> = 7, all in duplicate) were exposed to increasing concentrations (0–25 µM) of GW501516 and GSK0660 administered alone or in combination (0–10 µM) for four days. (<b>A</b>) The viability of HBFs was determined using an FDA+/EtBr- assay. (<b>B</b>) The proliferation rates were determined using a crystal violet assay, and the absorbances were measured spectrophotometrically (λ = 540 nm). The results are expressed as a percentage of the control and presented as the mean ± SEM. Statistical significance was tested using the nonparametric Kruskal–Wallis test with Dunn’s multiple comparisons post hoc test; * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001. The red box indicates the concentration used for further analyses (10 µM).</p> Full article ">Figure 2
<p>The profibrotic response of TGF-β<sub>1</sub>-stimulated HBFs was significantly attenuated by GW501516 when administered alone or in combination with GSK0660. HBFs derived from asthmatic patients were cultured in a serum-free medium containing GW501516 and GSK0660 alone or in combination, and in the absence or presence of TGF-β<sub>1</sub> (5 ng/mL) for four days. (<b>A</b>) The FMT potential of HBFs was determined via immunostaining for α-SMA (green) with DNA (blue) visualization. Representative images are presented. Scale bar = 50 µm. (<b>B</b>) The percentage of myofibroblasts in HBF cultures (<span class="html-italic">n</span> = 10) are presented in the graph. The α-SMA content in the HBFs was determined via (<b>C</b>) in-cell ELISA (<span class="html-italic">n</span> = 8; each condition in triplicate) and (<b>D</b>,<b>E</b>) Western blotting (<span class="html-italic">n</span> = 3). RCU–relative colorimetric units. The relative expressions of selected FMT-related genes: (<b>F</b>) <span class="html-italic">ACTA2</span> (α-smooth muscle actin), (<b>G</b>) <span class="html-italic">COL1A1</span>, (<b>H</b>) <span class="html-italic">COL1A2</span> (collagens 1a1 and 1a2), and (<b>I</b>) <span class="html-italic">TNC</span> (tenascin C), in HBFs (<span class="html-italic">n</span> = 5) cultured for 24 h under the conditions described above were determined via real-time PCR. The results are presented as 2<sup>−ΔΔCt</sup> mean values in relation to the control gene (<span class="html-italic">GAPDH</span>). The results are presented as the mean ± SEM. Statistical significance was tested using the nonparametric Kruskal–Wallis test with Dunn’s multiple comparisons post hoc test; * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 3
<p>The actin cytoskeleton architecture in TGF-β-treated HBFs was modulated by GW501516 alone or in combination with GSK0660. HBFs derived from asthmatic patients (<span class="html-italic">n</span> = 3) were cultured in a serum-free medium containing GW501516 and GSK0660 alone or in combination, and in the absence or presence of TGF-β<sub>1</sub> (5 ng/mL) for 24 h. (<b>A</b>) Representative images of HBFs immunostained for vinculin (green) and F-actin (red) with visualization of DNA (blue) are presented; scale bar = 50 µm. Vinculin-rich focal adhesion sites are shown enlarged in boxes; scale bar = 25 µm. (<b>B</b>) F-actin fluorimetry was quantified in relation to DNA fluorescence and is presented in the graph (<span class="html-italic">n</span> = 3, 260 cells/condition). (<b>C</b>) The lengths of vinculin-rich focal adhesion sites were measured and are presented in the graph. (<b>D</b>,<b>E</b>) The contents of focal-adhesion-related proteins vinculin and talin, were determined via in-cell ELISA (<span class="html-italic">n</span> = 8; each condition in triplicate). (<b>F</b>) The relative expression of <span class="html-italic">TLN</span> (talin) in HBFs (<span class="html-italic">n</span> = 3) cultured for 24 h under the conditions described above was determined using real-time PCR. The results are presented as 2<sup>−ΔΔCt</sup> mean values in relation to the control gene (<span class="html-italic">GAPDH</span>). RCU–relative colorimetric units. The results are presented as the mean ± SEM. Statistical significance was tested using the nonparametric Kruskal–Wallis test with Dunn’s multiple comparisons post hoc test; * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 4
<p>GW501516 and GSK0660, when administered alone or in combination, suppressed the TGF-β<sub>1</sub>-induced upregulation of Cx43 in HBF populations. HBFs derived from asthmatic patients were cultured in a serum-free medium containing GW501516 and GSK0660 alone or in combination, and in the absence or presence of TGF-β<sub>1</sub> (5 ng/mL) for four days. (<b>A</b>) Representative images of HBFs immunostained for Cx43 (red) with DNA visualization (blue) are presented. Scale bar = 50 µm. Cx43 levels in HBFs were determined via (<b>B</b>) the quantification of the fluorescence signal in the collected images (<span class="html-italic">n</span> = 5) or via (<b>C</b>) Western blot analyses (<span class="html-italic">n</span> = 1, densitometry is presented above the bands). (<b>D</b>) The relative expression of <span class="html-italic">GJA1</span> (the Cx43-encoding gene) in HBFs (<span class="html-italic">n</span> = 3) cultured for 24 h under the conditions described above was determined using real-time PCR. The results are presented as 2<sup>−ΔΔCt</sup> mean values in relation to the control gene (<span class="html-italic">GAPDH</span>). All results are presented as the mean ± SEM. Statistical significance was tested using the nonparametric Kruskal–Wallis test with Dunn’s multiple comparisons post hoc test; * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 5
<p>Canonical TGF-β<sub>1</sub>/Smad2-dependent signaling was modulated in HBFs in response to the administration of GW501516 and GSK0660 alone or in combination. HBFs derived from asthmatic patients were cultured in a serum-free medium containing GW501516 and GSK0660 alone or in combination, and in the absence or presence of TGF-β<sub>1</sub> (5 ng/mL) for 1 h. (<b>A</b>) Representative images of HBFs immunostained for pSmad2 (red) with DNA visualization (blue) are presented. Scale bar = 100 µm. (<b>B</b>) The number of cells expressing pSmad2 in the nuclei area was quantified. (<b>C</b>) The levels of pSmad2 in the nuclei area of HBFs were determined via the quantification of the fluorescence signal in the collected images (<span class="html-italic">n</span> = 4; 420 cells/condition). The relative expression of genes encoding (<b>D</b>) PPARδ (<span class="html-italic">PPARD</span>), (<b>E</b>) the p300 cofactor (<span class="html-italic">P300</span>), and (<b>F</b>) the Sox9 transcription factor (<span class="html-italic">SOX9</span>) were measured using real-time PCR. The results are presented as 2<sup>−ΔΔCt</sup> mean values in relation to the control gene (<span class="html-italic">GAPDH</span>). The results are presented as the mean ± SEM. Statistical significance was tested using the nonparametric Kruskal–Wallis test with Dunn’s multiple comparisons post hoc test; * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">

Review

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20 pages, 1986 KiB  
Review
Macrophage Functions in Psoriasis: Lessons from Mouse Models
by Katarzyna Nazimek and Krzysztof Bryniarski
Int. J. Mol. Sci. 2024, 25(10), 5306; https://doi.org/10.3390/ijms25105306 - 13 May 2024
Viewed by 899
Abstract
Psoriasis is a systemic autoimmune/autoinflammatory disease that can be well studied in established mouse models. Skin-resident macrophages are classified into epidermal Langerhans cells and dermal macrophages and are involved in innate immunity, orchestration of adaptive immunity, and maintenance of tissue homeostasis due to [...] Read more.
Psoriasis is a systemic autoimmune/autoinflammatory disease that can be well studied in established mouse models. Skin-resident macrophages are classified into epidermal Langerhans cells and dermal macrophages and are involved in innate immunity, orchestration of adaptive immunity, and maintenance of tissue homeostasis due to their ability to constantly shift their phenotype and adapt to the current microenvironment. Consequently, both macrophage populations play dual roles in psoriasis. In some circumstances, pro-inflammatory activated macrophages and Langerhans cells trigger psoriatic inflammation, while in other cases their anti-inflammatory stimulation results in amelioration of the disease. These features make macrophages interesting candidates for modern therapeutic strategies. Owing to the significant progress in knowledge, our review article summarizes current achievements and indicates future research directions to better understand the function of macrophages in psoriasis. Full article
(This article belongs to the Special Issue Advances in Experimental and Clinical Aspects of Allergies and Autoimmunity)
►▼ Show Figures

Figure 1

Figure 1
<p>Polarization of Langerhans cells (LC) and dermal macrophages in psoriasis. M1 macrophages play a deleterious role in psoriatic inflammation, while M2 macrophages are able to suppress this reaction. A shift of LCs and macrophages towards a proinflammatory M1 phenotype is induced by keratinocyte (KC) ferroptosis and by KC-released factors like antimicrobial peptides (AMPs), including LL-37-binding self RNA and DNA and triggering macrophage TLR7 and TLR8, high mobility group box 1 (HMGB1) protein recognized as a danger signal, as well as other understudied signals carried by extracellular vesicles (EVs). Furthermore, M1 macrophage infiltration is promoted by CX3CL1 acting via the CX3CR1 receptor. In addition, psoriasis-associated effector cytokines, including IL-17A from Th17 lymphocytes and γδ T cells and Th1 cell-derived IFNγ polarize macrophages towards the M1 phenotype. Conversely, IL-35 secreted by regulatory T (Treg) and B (Breg) lymphocytes together with topically and systemically administered medications promote the macrophage M2 phenotype. Moreover, a specific regulatory cell population, i.e., Treg-of-B cells, was found to increase the expression of STAT6 by macrophages in order to preserve their M2 polarization. Some of the icons were adopted from <a href="https://smart.servier.com/" target="_blank">https://smart.servier.com/</a> (accessed on 19 April 2024) and used in compliance with the terms of the Creative Commons Attribution 3.0 Unported License.</p> Full article ">Figure 2
<p>Postulated functions of Langerhans cells (LC) and dermal macrophages in autoimmune responses underlying plaque psoriasis. Psoriasis-inducing triggers stimulate keratinocytes (KCs) to release self-antigens (self-Ag), including self RNA and DNA, as well as antimicrobial peptides (AMPs), particularly LL-37. This drives pro-inflammatory activation of LC that present lipid antigens complexed with CD1a to γδ T cells. The latter cells secrete IL-17A under the influence of LC-derived IL-23. Some activated LCs migrate to draining lymph nodes where they present psoriasis-associated self-Ag to naive CD4+ T lymphocytes, as do dendritic cells (DCs), which are also capable of activating naive CD8+ T lymphocytes. LC- and DC-derived IL-23, IL-12, and TNFα stimulate CD4+ T cell differentiation towards Th17, Th1, and Th22 populations, respectively. Activated T lymphocytes migrate to the dermis where they initiate an autoimmune effector response. Th1 cell-derived IFNγ likely promotes Th17 cell differentiation and cytotoxic T (Tc) cell activity, and mostly stimulates macrophage cytotoxicity accompanied by generation of reactive oxygen species. This is also augmented by Tc cell-derived IFNγ and TNFα, while macrophages drive Tc cell activity through IL-23 release. Simultaneously, IL-22 increases the release of AMPs by KCs. Finally, IL-17A, together with TNFα derived from macrophages and Tc cells and IL-22 derived from Th22 cells, significantly enhances KC proliferation and impairs their differentiation, which leads to epidermal hyperplasia and the development of plaque psoriatic lesions. Some of the icons were adopted from <a href="https://smart.servier.com/" target="_blank">https://smart.servier.com/</a> (accessed on 19 April 2024) and used in compliance with the terms of the Creative Commons Attribution 3.0 Unported License.</p> Full article ">Figure 3
<p>Postulated functions of Langerhans cells (LCs) and dermal macrophages in generalized pustular psoriasis (GPP). GPP-inducing autoinflammatory triggers stimulate keratinocytes (KCs) to release IL-36 cytokine family members, including IL-36γ. After simultaneous secretion by LCs and dermal macrophages, IL-36γ acts in an autocrine and paracrine manner on these cells. As a result, LCs secrete IL-23 that induces IL-17 release by γδ T cells and Th17 lymphocytes. In parallel, dermal macrophages secrete IL-23 and TNFα that activate Th17 and Th22 lymphocytes, respectively. Released IL-17A stimulates the production of IL-8 (CXCL8) by KCs, which drives neutrophil infiltration and activation. Under the influence of neutrophils as well as macrophage-secreted TNFα, Th22 lymphocyte-derived IL-22, and IL-17A, KCs release significant amounts of IL-36 precursors that are activated by KC-derived cathepsin S and neutrophil-derived proteases, such as elastase, cathepsin G, and protease 3, released mostly during the formation of neutrophil extracellular traps. The latter is accompanied by the release of antimicrobial peptides (AMPs) by neutrophils and KCs. A continuously driven IL-36-dependent positive feedback loop leads to the pro-inflammatory activation of KCs and neutrophil accumulation that results in GPP development. Some of the icons were adopted from <a href="https://smart.servier.com/" target="_blank">https://smart.servier.com/</a> (accessed on 19 April 2024) and used in compliance with the terms of the Creative Commons Attribution 3.0 Unported License.</p> Full article ">Figure 4
<p>Antipsoriatics that directly affect the activity of Langerhans cells (LCs) and dermal macrophages. Macrophages degrade cyclic adenosine monophosphate (cAMP) into AMP using phosphodiesterase-4 (PDE-4), which activates nuclear factor kappa B (NF-κB)-dependent signaling that leads to the production of pro-inflammatory cytokines, including IL-23 and TNFα. This signaling circuit can be therapeutically inhibited at various stages. Orally administered apremilast and topically applied roflumilast efficiently inhibit PDE-4 activity, while dimethyl fumarate, a first-line systemic therapeutic for plaque psoriasis, blocks the activity of the NF-κB transcription factor, thereby preventing the production of pro-inflammatory cytokines. Finally, various monoclonal antibodies (mAbs) that neutralize specific cytokines have already been approved for the treatment of psoriasis. These include anti-TNFα mAbs such as Infliximab, Adalimumab, and Certolizumab pegol, as well as Ustekinumab, which binds to the p40 subunit shared by IL-12 and IL-23, and mAbs directed against IL-23p19 subunit, e.g., Guselkumab and Tildrakizumab. Some of the icons were adopted from <a href="https://smart.servier.com/" target="_blank">https://smart.servier.com/</a> (accessed on 7 May 2024) and used in compliance with the terms of the Creative Commons Attribution 3.0 Unported License.</p> Full article ">
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