Alvaro López Malizia
@inbirs.org.ar
INSTITUTE OF BIOMEDICAL RESEARCH IN RETROVIRUS AND AIDS (INBIRS)
RESEARCH, TEACHING, or OTHER INTERESTS
Immunology and Allergy, Molecular Biology, Molecular Medicine, Cancer Research
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Ana Paletta, Facundo Di Diego García, Augusto Varese, Fernando Erra Diaz, Julián García, Juan Carlos Cisneros, Guillermina Ludueña, Ignacio Mazzitelli, Andrea Pisarevsky, Gonzalo Cabrerizo,et al.
Wiley
SummarySevere COVID‐19 is associated with a systemic inflammatory response and progressive CD4+ T‐cell lymphopenia and dysfunction. We evaluated whether platelets might contribute to CD4+ T‐cell dysfunction in COVID‐19. We observed a high frequency of CD4+ T cell–platelet aggregates in COVID‐19 inpatients that inversely correlated with lymphocyte counts. Platelets from COVID‐19 inpatients but not from healthy donors (HD) inhibited the upregulation of CD25 expression and tumour necrosis factor (TNF)‐α production by CD4+ T cells. In addition, interferon (IFN)‐γ production was increased by platelets from HD but not from COVID‐19 inpatients. A high expression of PD‐L1 was found in platelets from COVID‐19 patients to be inversely correlated with IFN‐γ production by activated CD4+ T cells cocultured with platelets. We also found that a PD‐L1‐blocking antibody significantly restored platelets’ ability to stimulate IFN‐γ production by CD4+ T cells. Our study suggests that platelets might contribute to disease progression in COVID‐19 not only by promoting thrombotic and inflammatory events, but also by affecting CD4+ T cells functionality.
Antonela Merlotti, Alvaro López Malizia, Paula Michea, Pierre-Emmanuel Bonte, Christel Goudot, María Sol Carregal, Nicolás Nuñez, Christine Sedlik, Ana Ceballos, Vassili Soumelis,et al.
Informa UK Limited
ABSTRACT Clusterin is a glycoprotein able to mediate different physiological functions such as control of complement activation, promotion of unfolded protein clearance and modulation of cell survival. Clusterin is overexpressed in many types of cancers and a large body of evidence suggests that it promotes carcinogenesis and tumor progression. We have previously described a novel clusterin glycoform present in human semen, but not in serum, highly enriched in terminal fucose motifs. Here we show that human luminal breast cancer (LBC) clusterin also bears terminal fucosylated glycans, conferring clusterin the ability to interact with DC-SIGN, a C-type lectin receptor expressed by myeloid cells. This clusterin glycosylation pattern was absent or diminished in non-involved juxtatumoral tissue, suggesting that fucosylated clusterin might represent a cancer associated glycoform. We also found that DC-SIGN is expressed by luminal breast cancer intratumoral macrophages. Moreover, experiments performed in vitro using semen fucosylated clusterin and monocyte derived macrophages showed that the interaction of semen clusterin with DC-SIGN promoted a proangiogenic profile, characterized by a high production of VEGF, IL-8 and TNF-α. Our results reveal an unexpected complexity on the structure and function of secretory clusterin produced by tumors and suggest that fucosylated clusterin produced by luminal breast cancer cells might play a role in tumor progression by promoting the release of pro-angiogenic factors by intratumoral macrophages.
Federico Remes Lenicov, Ana Luz Paletta, Melina Gonzalez Prinz, Augusto Varese, Clara E. Pavillet, Álvaro Lopez Malizia, Juan Sabatté, Jorge Raul Geffner, and Ana Ceballos
Frontiers Media SA
Inflammatory dendritic cells (DCs) are a distinct subset of DCs that derive from circulating monocytes infiltrating injured tissues. Monocytes can differentiate into DCs with different functional signatures, depending on the presence of environment stimuli. Among these stimuli, transforming growth factor-beta (TGF-β) and prostaglandin E2 (PGE2) have been shown to modulate the differentiation of monocytes into DCs with different phenotypes and functional profiles. In fact, both mediators lead to contrasting outcomes regarding the production of inflammatory and anti-inflammatory cytokines. Previously, we have shown that human semen, which contains high concentrations of PGE2, promoted the differentiation of DCs into a tolerogenic profile through a mechanism dependent on signaling by E-prostanoid receptors 2 and 4. Notably, this effect was induced despite the huge concentration of TGF-β present in semen, suggesting that PGE2 overrides the influence exerted by TGF-β. No previous studies have analyzed the joint actions induced by PGE2 and TGF-β on the function of monocytes or DCs. Here, we analyzed the phenotype and functional profile of monocyte-derived DCs differentiated in the presence of TGF-β and PGE2. DC differentiation guided by TGF-β alone enhanced the expression of CD1a and abrogated LPS-induced expression of IL-10, while differentiation in the presence of PGE2 impaired CD1a expression, preserved CD14 expression, abrogated IL-12 and IL-23 production, stimulated IL-10 production, and promoted the expansion of FoxP3+ regulatory T cells in a mixed lymphocyte reaction. Interestingly, DCs differentiated in the presence of TGF-β and PGE2 showed a phenotype and functional profile closely resembling those induced by PGE2 alone. Finally, we found that PGE2 inhibited TGF-β signaling through an action exerted by EP2 and EP4 receptors coupled to cyclic AMP increase and protein kinase A activity. These results indicate that PGE2 suppresses the influence exerted by TGF-β during DC differentiation, imprinting a tolerogenic signature. High concentrations of TGF-β and PGE2 are usually found in infectious, autoimmune, and neoplastic diseases. Our observations suggest that in these scenarios PGE2 might play a mandatory role in the acquisition of a regulatory profile by DCs.