SUBTLE MODULATION OF GALECTIN-1 FUNCTION BY THE ACIDIC MICROENVIRONMENT

DI LELLA, SANTIAGO; MÉNDEZ-HUERGO, SANTIAGO; ROMERO, JUAN MANUEL; GALLO, MARIANA; ESTRIN, DARÍO ARIEL; CARAMELO, JULIO JAVIER; RABINOVICH, GABRIEL ADRIÁN

Ventura, California, EEUU

Conferencia; Gordon Research Conference - Glycobiology; 2013

Gordon Research Conferences

Galectin-1 (Gal1), an endogenous lectin able to recognize multiple N-Acetil-lactosamine units in a wide variety of  cells and tissues, displays an homeostatic role in the regulation of innate and adaptive immunity. Its anti-inflammatory and immunosuppressive  activity has been evidenced in a variety of autoimmune and cancer models. Functional studies of Gal1 have been commonly developed at the physiological pH of 7,4. However, the inflammatory micro-environment   has particular physico-chemical properties.  Among them, pH appears as a key factor, provided that the inflammatory tissues display a considerable acidity (extreme acidosis, pH 5.2). The aim of this study is to understand the impact of pH fluctuations in Gal1 immunomodulatory activity by means of a multidisciplinary approach, ranging from cellular assays to biophysical and structural studies. Results evidenced an association between the acidic environment and the proapoptotic activity of Gal1 in PBMCs. This association was further investigated with in-vitro cell binding assays, followed by fluorescence and NMR studies, yielding a structural explanation for the aforementioned results. Furthermore, we performed molecular dynamics simulations of this lectin, providing an atomistic interpretation of the changes observed. Taken together, these results reveal the influence of the acidic micro-environment in the immunomodulatory activity of Gal-1,  which has critical implications in the regulation of the activity and therapeutic potential of this protein during chronic inflammatory responses.