Cyclophilin A is an endogenous ligand for the triggering receptor expressed on myeloid cells‐2 (TREM2)

Ji, Kon-Young; Kim, Su-Man; Yee, Su-Min; Kim, Minjae; Ban, Yu-Jin; Kim, Eun‐Mi; Lee, Eun-Hee; Choi, Hyungsub; Yun, Hyosuk; Lee, Chul Won; Yun, Chul‐Ho; Lee, C Justin; Lee, Hyang Burm; Kang, Hyung‐Sik

doi:10.1096/fj.202002325rr

Cited by 14 publications

(10 citation statements)

References 36 publications

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“…Besides ACE2, other molecules seem to participate in SARS‐CoV‐2 infection, 7 including several molecules that might be involved in SARS‐CoV‐2 cell susceptibility, such as Neuropilin 1 and cluster of differentiation 147 (CD147), cyclophilin A, reported to be associated with enhanced viral infection 8–12 …”

Section: Introductionmentioning

confidence: 99%

Relevance of VEGF and CD147 in different SARS‐CoV‐2 positive digestive tracts characterized by thrombotic damage

et al. 2021

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Several evidence suggests that, in addition to the respiratory tract, also the gastrointestinal tract is a main site of severe acute respiratory syndrome CoronaVirus 2 (SARS‐CoV‐2) infection, as an example of a multi‐organ vascular damage, likely associated with poor prognosis. To assess mechanisms SARS‐CoV‐2 responsible of tissue infection and vascular injury, correlating with thrombotic damage, specimens of the digestive tract positive for SARS‐CoV‐2 nucleocapsid protein were analyzed deriving from three patients, negative to naso‐oro‐pharyngeal swab for SARS‐CoV‐2. These COVID‐19–negative patients came to clinical observation due to urgent abdominal surgery that removed different sections of the digestive tract after thrombotic events. Immunohistochemical for the expression of SARS‐CoV‐2 combined with a panel of SARS‐CoV‐2 related proteins angiotensin‐converting enzyme 2 receptor, cluster of differentiation 147 (CD147), human leukocyte antigen‐G (HLA‐G), vascular endothelial growth factor (VEGF) and matrix metalloproteinase‐9 was performed. Tissue samples were also evaluated by electron microscopy for ultrastructural virus localization and cell characterization. The damage of the tissue was assessed by ultrastructural analysis. It has been observed that CD147 expression levels correlate with SARS‐CoV‐2 infection extent, vascular damage and an increased expression of VEGF and thrombosis. The confirmation of CD147 co‐localization with SARS‐CoV‐2 Spike protein binding on gastrointestinal tissues and the reduction of the infection level in intestinal epithelial cells after CD147 neutralization, suggest CD147 as a possible key factor for viral susceptibility of gastrointestinal tissue. The presence of SARS‐CoV‐2 infection of gastrointestinal tissue might be consequently implicated in abdominal thrombosis, where VEGF might mediate the vascular damage.

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Section: Introductionmentioning

confidence: 99%

Relevance of VEGF and CD147 in different SARS‐CoV‐2 positive digestive tracts characterized by thrombotic damage

et al. 2021

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“…Since its discovery, the identification of endogenous ligands of TREM2 has proven elusive although there is an emerging pattern of evidence suggesting that the receptor can interact with a wide array of negatively charged molecules mostly associated to tissue damage or cellular stress [ 19 – 22 ]. Except for the reports on the binding of the ubiquitous protein cyclophilin A [ 23 ] and a X-ray crystallography model of TREM2 centered on a prominent surface of positively charged residues [ 24 ], most studies are related to the affinity of putative ligands with the receptor [ 11 ]. For this reason, in order to test the binding of SULF A to TREM2, we used a consolidated TREM2-reporter cell line that transduces receptor engagement by synthesis of GFP [ 20 ].…”

Section: Resultsmentioning

confidence: 99%

“…The downstream cascade signal of TREM2 is mediated by the electrostatic interaction with DNAX-activation protein 12 (DAP12) [ 11 , 13 ] that, upon phosphorylation, recruits SYK and initiates the intracellular pathway. The next steps are not fully elucidated but independent authors reported that TREM2-mediated activity depends on NFAT [ 20 , 26 , 27 ], a family of five transcription factors which are mostly regulated by Ca 2+ . In striking contrast to the response to C-type lectins, such as dectins or mincle, that requires NFAT together with canonical and non-canonical pathways of nuclear factor-B (NF-kB) in DCs and macrophages [ 28 ], 28 ], TREM2 signaling transduction is independent of NF-κB in DCs [ 30 ].…”

Section: Resultsmentioning

confidence: 99%

Sulfavant A as the first synthetic TREM2 ligand discloses a homeostatic response of dendritic cells after receptor engagement

Gallo

Manzo

Barra

et al. 2022

Cell. Mol. Life Sci.

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Objective The immune response arises from a fine balance of mechanisms that provide for surveillance, tolerance, and elimination of dangers. Sulfavant A (SULF A) is a sulfolipid with a promising adjuvant activity. Here we studied the mechanism of action of SULF A and addressed the identification of its molecular target in human dendritic cells (hDCs). Methods Adjuvant effect and immunological response to SULF A were assessed on DCs derived from human donors. In addition to testing various reporter cells, target identification and downstream signalling was supported by a reverse pharmacology approach based on antibody blocking and gene silencing, crosstalk with TLR pathways, use of human allogeneic mixed lymphocyte reaction. Results SULF A binds to the Triggering Receptor Expressed on Myeloid cells-2 (TREM2) and initiates an unconventional maturation of hDCs leading to enhanced migration activity and up-regulation of MHC and co-stimulatory molecules without release of conventional cytokines. This response involves the SYK-NFAT axis and is compromised by blockade or gene silencing of TREM2. Activation by SULF A preserved the DC functions to excite the allogeneic T cell response, and increased interleukin-10 release after lipopolysaccharide stimulation. Conclusion SULF A is the first synthetic small molecule that binds to TREM2. The receptor engagement drives differentiation of an unprecedented DC phenotype (homeDCs) that contributes to immune homeostasis without compromising lymphocyte activation and immunogenic response. This mechanism fully supports the adjuvant and immunoregulatory activity of SULF A. We also propose that the biological properties of SULF A can be of interest in various physiopathological mechanisms and therapies involving TREM2.

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“…The downstream cascade signal of TREM2 is mediated by the electrostatic interaction with DNAXactivation protein 12 (DAP12) [11,13] that, upon phosphorylation, recruits SYK and initiates the intracellular pathway. The next steps are not fully elucidated but independent authors reported that TREM2-mediated activity depends on NFAT [17,21,22], a family of ve transcription factors which are mostly regulated by Ca 2+ . In striking contrast to the response to C-type lectins, such as dectins or mincle, that requires NFAT together with canonical and non-canonical pathways of nuclear factor-kB (NF-kB) in DCs and macrophages [23][24], TREM2 signaling transduction is independent of NF-kB in DCs [25].…”

Section: Transcriptional Regulation Of Intracellular Trem2 Signaling By Sulf Amentioning

confidence: 99%

Identification of Sulfavant A as the First Synthetic TREM2 Ligand Discloses a Homeostatic Response of Dendritic Cells After Receptor Engagement

Gallo

Manzo

Barra

et al. 2022

Preprint

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The immune response arises from a fine balance of cellular and molecular mechanisms that provide for surveillance, tolerance, and elimination of dangers as pathogens. Improving the quality of the immune response remains a major goal in immunotherapy and vaccine development. Sulfavant A (SULF A) is a sulfolipid that has shown promising adjuvant activity in a cancer vaccine model. Here we report that SULF A is the first synthetic small molecule binding to the Triggering Receptor Expressed on Myeloid cells-2 (TREM2). The receptor engagement initiates an unconventional maturation of Dendritic cells (DCs) leading to upregulation of the Major Histocompatibility Complex class II (MHC Class II) and costimulatory molecules (CD83, CD86, DC54) without release of T helper type 1 (Th1) or 2 (Th2) cytokines. According to a TREM2 mechanism, this response is mediated by SYK-NFAT axis and is compromised by blockade and gene silencing of the receptor. Activation by SULF A preserved the DC functions to excite the allogeneic T cell response, and induced interleukin-10 (IL-10) release after lipopolysaccharide (LPS) stimulation. These results well support the adjuvant effect of SULF A and offer novel insights into the role of TREM2 in the differentiation of an unprecedented DC phenotype (homeDCs) that contributes to the maintenance of immune homeostasis without compromising lymphocyte activation and immunogenic response. The biological function of SULF-A may be of interest in various physiological and pathological processes involving the immune system.

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Cyclophilin A is an endogenous ligand for the triggering receptor expressed on myeloid cells‐2 (TREM2)

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 14 publications

References 36 publications

Relevance of VEGF and CD147 in different SARS‐CoV‐2 positive digestive tracts characterized by thrombotic damage

Relevance of VEGF and CD147 in different SARS‐CoV‐2 positive digestive tracts characterized by thrombotic damage

Sulfavant A as the first synthetic TREM2 ligand discloses a homeostatic response of dendritic cells after receptor engagement

Identification of Sulfavant A as the First Synthetic TREM2 Ligand Discloses a Homeostatic Response of Dendritic Cells After Receptor Engagement

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