IL-17 and Therapeutic Kynurenines in Pathogenic Inflammation to Fungi

Abstract

Largely viewed as proinflammatory, innate responses combine with adaptive immunity to generate the most effective form of antifungal resistance, and T cells exercise feedback control over diverse effects of inflammation on infection. Some degree of inflammation is required for protection, particularly in mucosal tissues, during the transitional response occurring between the rapid innate and slower adaptive response. However, progressive inflammation worsens disease and ultimately prevents pathogen eradication. IDO, tryptophan catabolites (“kynurenines”), and regulatory T cells help to tame overzealous and exaggerated inflammatory responses. In this context, IL-23 and the Th17 pathway, which down-regulate tryptophan catabolism, may instead favor pathology and serve to accommodate the seemingly paradoxical association of chronic inflammation with fungal persistence. Recent data support a view in which IL-23/IL-17 antagonistic strategies, including the administration of synthetic kynurenines, could represent a new means of harnessing progressive or potentially harmful inflammation.

Generation of mesenchymal stromal cells in the presence of platelet lysate: a phenotypic and functional comparison of umbilical cord blood- and bone marrow-derived progenitors

“…The results obtained in our study suggest that UCB-MSC are able to exert an immunosuppressive effect on alloantigen-specific immune responses through several mechanisms, including IDO activation and production of kynurenine, PGE2 secretion and HLA-G expression. 4,11,36,[43][44][45][46][47][48][49] All these biological mechanisms have been previously described to be active in MSC derived from other sources, such as BM-MSC. 4,11,35,[43][44][45][46][47][48][49] In particular, it is noteworthy that our data confirm and extend previously reported results, underlining the inter-relationship between PGE2 secretion and IDO activation, two well-known mechanisms involved in the antiinflammatory immune response.…”

“…48 Moreover, surface HLA-G expression is one of the systems employed by tumor cells to evade the cytotoxic activity of both tumor-specific T lymphocytes and NK cells, and it has been recently suggested that transfer of membrane patches containing HLA-G molecules from membrane HLA-G + cells to activated T and NK lymphocytes (trogocytosis) might be a mechanism of immune suppression protecting HLA-G -tumor cells. 49 It may, thus, be speculated that UCB-MSC expressing membrane HLA-G may be more protected than BM-MSC from attack mediated by the host immune system. However, it has recently been demonstrated in a murine model that while local implantation of MSC results in ectopic bone formation in syngeneic recipients, it leads to transplant rejection in allogeneic mice.…”

High doses of CpG oligodeoxynucleotides stimulate a tolerogenic TLR9–TRIF pathway

“…These data demonstrate that CpG downregulates exacerbating Th2 responses in ABPA by inhibiting the expansion and activation of Th2 cells, and upregulates Foxp3 expression via mechanisms that require TLR9 and TRIF but not MyD88. It is interesting to note that in the model of ABPA, resident pDCs will confer protective tolerance to Aspergillus 37 and that protection can be adoptively transferred by pulsed DCs that exploit anti-inflammatory, IDO-dependent pathways 38 , involving Treg cell generation 39 .…”

Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO

“…6 As a matter of fact, IL-23 produced by inflammatory DCs and the T helper 17 (Th17) pathway, which downregulate tryptophan catabolism, favored pathology and served to accommodate the seemingly paradoxical association of chronic inflammation with fungal persistence. [10][11][12] No longer considered innocent bystanders, 13 airway epithelial cells (ECs) are central participants in innate and adaptive immune responses as well as mucosal inflammation and allergy. 14 Through the activation of Toll-like receptors (TLRs) by endogenous and exogenous ligands, ECs may play a central role in determining the balance between a state of 'mucosal homeostasis', as is required for optimal organ function, and 'mucosal injury', leading to mucosal inflammation and barrier breakdown.…”