Autophagy and mitochondrial remodelling in mouse mesenchymal stromal cells challenged with Staphylococcus epidermidis

Abstract

The bone marrow stroma constitutes the marrow-blood barrier, which sustains immunochemical homoeostasis and protection of the haematopoietic tissue in sequelae of systemic bacterial infections. Under these conditions, the bone marrow stromal cells affected by circulating bacterial pathogens shall elicit the adaptive stress-response mechanisms to maintain integrity of the barrier. The objective of this communication was to demonstrate (i) that in vitro challenge of mesenchymal stromal cells, i.e. colony-forming unit fibroblasts (CFU-F), with Staphylococcus epidermidis can activate the autophagy pathway to execute antibacterial defence response, and (ii) that homoeostatic shift because of the bacteria-induced stress includes the mitochondrial remodelling and sequestration of compromised organelles via mitophagy. Implication of Drp1 and PINK1–PARK2-dependent mechanisms in the mitophagy turnover of the aberrant mitochondria in mesenchymal stromal cells is investigated and discussed.

Introductory Chapter: Overview on Autophagy in Burden of Functions

“…Thus, a lack of the "canonical" phagocytic features (such as phagosome biogenesis, the oxidative burst, etc.) in nonprofessional phagocytes is presumably compensated by empowering xenophagy to control and execute all events from pathogen sequestration through degradation [5,6,[18][19][20][21], current book Chpt. 15].…”

“…From this perspective, while macroautophagy, microphagy and chaperone-mediated autophagy execute barrier functions at molecular and membrane levels [2,5,6,[13][14][15][16][17], it would be reasonable to assume that dynamics and efficacy of autophagy function can determine performance of the barrierforming cells. Note, in the vertebrates the infection cellular barriers are constituted by multidimensional interactive networks of mesenchymal, epithelial, reticuloendothelial, endothelial and hematopoietic cells, where along with monocytes and polymorphonuclear granulocytes, a particular role in xenobiotic control and "cleaning function" is attributed to nonprofessional phagocytes, e.g., skin fibroblasts, bone marrow stromal cells, endothelial and epithelial cells [18,19]. Evidently, nonprofessional phagocytes are very efficient in phagocytosis with "autophagy-to-pathogen" response mechanism and therefore, can compensate professional phagocyte function, when the last one declines [19].…”

“…Note, in the vertebrates the infection cellular barriers are constituted by multidimensional interactive networks of mesenchymal, epithelial, reticuloendothelial, endothelial and hematopoietic cells, where along with monocytes and polymorphonuclear granulocytes, a particular role in xenobiotic control and "cleaning function" is attributed to nonprofessional phagocytes, e.g., skin fibroblasts, bone marrow stromal cells, endothelial and epithelial cells [18,19]. Evidently, nonprofessional phagocytes are very efficient in phagocytosis with "autophagy-to-pathogen" response mechanism and therefore, can compensate professional phagocyte function, when the last one declines [19]. Thus, a lack of the "canonical" phagocytic features (such as phagosome biogenesis, the oxidative burst, etc.)…”

“…That infers increasing burden of autophagy function in nonprofessional phagocytes when professional phagocytes are depleted due to pathological conditions. Furthermore, considering that nonprofessional phagocytes can also orchestrate response to acute stress or trauma by expression and massive release of paracrine and endocrine factors, such as damage-associated molecular patterns (DAMPs), inflammatory cytokines, proteases, chemokines, defensins, nitric oxide, ROS, fragmented DNA, exosomes and microvesicles, which in turn can trigger and propagate autophagy stress response [6,[14][15][16][17][18][19].…”

“…While in the second case the signaling mechanism is initiated by mitochondrial expression of either Nix/Bnip3L and Bnip3 receptors of LC3/GABARAP or-PINK1 kinase followed by recruitment of cytosolic Parkin (E3 ubiquitin ligase), Mfn2, ubiquitin and p62 linking the mitochondrial cargo with LC3/GABARAP on isolation membrane [5,6]. Seemingly, host cells endowed with these signaling mechanisms are capable of pursuing selective "multitargeting" autophagy, and thus sustaining resistance to invading pathogens, pathogenic factors as well as to the associated damage to mitochondria and ER [19].…”