Functional properties of galectin-3. Beyond the sugar binding.

• Contemporary diseases like diabetes, asthma, atherosclerosis etc. are marked by chronic inflammation, often supported by the activity of different macrophages. Proteins from galectin family were found to contribute to disease pathophysiology. Therefore, there is an intensive interest in understanding different galectin functions. The aim of this thesis was to pin-point specific galectin-3 roles in differently activated macrophages. Additional aim was to understand the mechanism and consequences of galectin-3 ligand binding. In the first paper galectin-3 endocytosis was studied in a system of differently activated macrophages. We found that inflammatory, M1, and alternatively activated, M2, macrophages have a large capacity to internalize externally added galectin-3, besides expressing and secreting galectin-3. Additionally, we found that galectin-3 does not require the functional carbohydrate recognition domain (CRD) for its endocytosis. In the second paper we used M2 macrophages to study how galectin-1 directs the endocytosis of hemoglobin-haptoglobin complex. Our results indicated that galectin-1 bound fraction of the complex takes a recycling intracellular route instead of the pathway for degradation. The third paper shows how certain complex carbohydrate ligands can induce galectin-3 self-association that involves CRD to CRD binding. This “type-C” self-association engages more galectin-3 molecules than there are available glycan ligands and can explain certain biological events that require fast galectin-3 mobilization. In the fourth paper we tested the inhibitory potential of a few plant products for several galectins. We found that their activity was very weak, hence the search for more potent anti-galectin, perhaps also anti-inflammatory remedies continues.

• Popular Abstract in Uncoded languages Kronična upala je u podlozi mnogih bolesti modernog čovjeka kao što su djiabetes, astma, ateroskleroza itd. Upalu predvode različiti tkivni makrofagi. Proteini iz porodice galektina, proizvedeni u makrofagima, dodatno pridonose razvoju bolesti, stoga je od velikog interesa odgonetnuti različite funkcije galektina. Ovaj rad nastoji identificirati specifične uloge galektina-3 u različito aktiviranim makrofagima te razumjeti mehanizam i posljedice vezanja galektina-3 za ligand. U prvom radu proučavali smo endocitozu galektina-3 u različito aktiviranim makrofagima. Vidjeli smo da upalni, M1, i alternativno aktivirani, M2, makrofagi proizvode i izlučuju galektin-3 te također mogu endocitozom unositi velike količine galektina-3 dodanog iz vana. Domena koja prepoznaje ugljikohidrat galektina-3 (CRD) nije bila neophodna za endocitozu. Drugi rad proučava mehanizam kojim galektin-1 usmjerava endocitozu hemoglobinsko-haptoglobinskog kompleksa u M2 makrofagima. Rezultati ukazuju da se galektin-1 dijelom veže na kompleks te ga usmjerva unutar stanice, zaobilazeći put razgradnje, možda u korist recikliranja. Treći rad bavi se samozdruživanjem galektina-3 koje se ostvaruje kroz međusobnu interkaciju CRD galektina-3. Takav tip samozdruživanja (tip-C) može inicirati samo određeni tip složenog ugljikohidratnog liganda. U vezanje je uključeno više molekula galektina-3 nego što je rasploživog liganda, stoga proces podržava brzu mobilizaciju galktina-3. U zadnjem radu testirali smo nekolicinu biljnih prerađevina u potrazi za galektinskim inhibitorima. Pokazali smo da određeni biljni produkti vrlo slabo djeluju na nekoliko testiranih galektina. Djelotvnorni galektinski inhibitori su i potencijalni protuupalni lijelovi te bi njihov pronalazak i razvoj mogao biti od velike koristi.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Immunology in the medical area (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Mikrobiologi inom det medicinska området (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Microbiology in the medical area (hsv//eng)

Keyword

galectin-3

galectin-1

M1 macrophage

M2 macrophage

self-association

fluorescence anisotropy

citrus pectin

galactomannane

Publication and Content Type

dok (subject category)

vet (subject category)