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Nail psoriasis
Published in Archana Singal, Shekhar Neema, Piyush Kumar, Nail Disorders, 2019
The increased dermal T-lymphocytes are a mixture of CD4+ and CD8+ cells, with CD4+ predominance. Most T cells in skin lesions are memory cells that express cutaneous lymphocyte antigen (CLA). Recently, γδ T cells have been found to be the IL-17-producing cells in psoriasis. IL-17 is now considered a key cytokine in the formation of the psoriatic phenotype and many of the genes induced by this cytokine in keratinocytes are highly expressed in psoriasis lesions, including chemokines and antimicrobial peptides (AMPs). IL-17 induces IL-19 and IL-36γ in psoriasis lesions, which may then lead to proliferative responses in keratinocytes. IL-20 and IL-22 have similar trophic effects on the epidermis.8,9
Inflammation in Psoriasis and Psoriatic Arthritis
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
IL-36 is a set of cytokines belonging to the IL-1 family, which includes three agonists, namely, IL-36α, IL-36β, and IL-36γ, and an IL-36 receptor antagonist (IL-36Ra). Agonistic IL-36 receptor (IL-36R) ligation leads to intracellular signals similar to those induced by IL-1. Epithelial cells constitutively express IL-36 agonists and IL-36Ra, where they act as primary defense mechanisms at the skin barrier. Knockout data from transgenic mice suggest that IL-36, in contrast to IL-1, is not involved in the development of experimental arthritis [28].
Genetics
Published in M. Alan Menter, Caitriona Ryan, Psoriasis, 2017
Loss-of-function amino acid substitutions in IL36RN are found in some cases of pustular Ps and behave as recessive traits.79,80 The mutated protein leads to an increased production of proinflammatory cytokines, such as IL-8, from keratinocytes. IL36RN mutations are also found in some patients with severe acute generalized exanthematous pustulosis, palmar–plantar pustulosis, and acrodermatitis continua of hallopeau.81 The protein encoded by IL36RN directly opposes the activity of IL-36γ and also intersects with the NF-κB pathway. As described earlier, a sporadic mutation in the coiled-coil domain of CARD14, leading to a p.E138A alteration, triggered generalized pustular Ps.8 Determining whether and where activation pathways for CARD14 and IL-36RN intersect requires further evaluation.
Luteolin alleviated neutrophilic asthma by inhibiting IL-36γ secretion-mediated MAPK pathways
Published in Pharmaceutical Biology, 2023
Xin-rui Qiao, Tao Feng, Dong Zhang, Li-li Zhi, Jin-tao Zhang, Xiao-fei Liu, Yun Pan, Jia-wei Xu, Wen-Jing Cui, Liang Dong
The research showed that the expression of IL-36γ in neutrophilic asthma was significantly increased in animal models, and luteolin played an important anti-inflammatory role in neutrophilic asthma. Combined with in vitro experiments, the specific anti-inflammatory mechanism of luteolin in neutrophil asthma inflammation was further demonstrated. We suspect that in the development and progression of neutrophilic asthma, its trigger factors (e.g., LPS) stimulate the airway and promote the secretion of IL-36γ in airway epithelial cells. IL-36γ up-regulates the expression of IL-1β through the MAPK pathway, and IL-1β promotes the secretion of IL-36γ, thus amplifying the inflammatory response. Luteolin can break this positive feedback by blocking the induction of IL-1β by IL-36γ in human bronchial epithelial cells, thus reducing the secretion of inflammatory factors and alleviating the inflammatory response (Figure 7). Whether this conjecture is true remains to be further explored to prove that IL-1β can promote the secretion of IL-36γ in the Beas-2B cells.
Advances in engineering and delivery strategies for cytokine immunotherapy
Published in Expert Opinion on Drug Delivery, 2023
Margaret Bohmer, Yonger Xue, Katarina Jankovic, Yizhou Dong
LNPs are also being created to deliver multiple mRNAs for cytokines and ligands. mRNA-2752 is an LNP containing mRNAs for O×40 L, IL-36γ, and IL-23 [113]. O×40 L is a ligand that activates the O×40 tumor necrosis factor receptor, also known as CD134. When O×40 L binds to the O×40 receptor on T cells, it promotes T-cell survival and cytokine production [114]. IL-36γ and IL-23 are both pro-inflammatory cytokines that were included to increase inflammation in the TME. In preclinical studies, this treatment led to systemic immunity and tumor regression in mice [113]. In a phase I clinical trial, mRNA-2752 was administered alone or combined with durvalumab, a PD-L1 inhibitor, to patients with solid tumors (Figure 5a). Biomarker analyses showed that the combination therapy caused elevated IFN-γ (Figure 5b) and TNF-α (Figure 5c) [115]. Another LNP in clinical trials is MEDI1191, which contains IL-12 mRNA. A phase I trial of a combination with durvalumab is ongoing, but thus far has shown limited toxicity [116]. Additionally, LNPs were recently used to encapsulate IL-12- and IL-27-encoding mRNAs. These LNPs contained a novel di-amino ionizable lipid that led to tumor growth suppression without systemic toxicity in mice [117].
Biologic insights from single-cell studies of psoriasis and psoriatic arthritis
Published in Expert Opinion on Biological Therapy, 2022
Joy Q Jin, David Wu, Riley Spencer, Kareem G Elhage, Jared Liu, Mitchell Davis, Marwa Hakimi, Sugandh Kumar, Zhi-Ming Huang, Tina Bhutani, Wilson Liao
Park et al. established keratinocytes as a source of IL-23A and IL-12B in PSO lesions from two scRNA-seq datasets, with PSO keratinocytes additionally upregulating the expression of IL36G [33]. In this study, inducible production of the IL-23p19 subunit was also observed in suprabasal keratinocytes in imiquimod-induced PSO mouse models. Moreover, IL-23 in combination with IL-12 was a stimulus for IL36G expression in a keratinocyte but not a T cell derived cell line. This finding was clinically corroborated: patients with similar PASI scores demonstrated reduced IL-36γ expression in keratinocytes when treated with anti-IL-12/23 p40 antibodies rather than methotrexate [33]. IL-36γ is a keratinocyte-derived cytokine known to be an important factor in generalized pustular PSO and plaque PSO, and serves as an upstream and downstream signaling molecule of IL-23 [34,35].