A Janus role for MerTK in the outcome of septic shock

Abstract

Severe sepsis remains a clinical challenge today, even indeveloped countries, because of the increased age of thepatients and the high burden of antibiotic resistance [1]. Inaddition, in recent years, we have become increasinglyaware that, even in the early stages of sepsis, a high pro-portion of patients experience a severe dysfunction ofnative and adaptive immunity, which is closely related topatients’ outcome [2]. In this context, understanding thefunctionality of receptors able to modulate the immuneresponse, and in particular to downregulate inflammation,has great importance for designing new therapeutic strat-egies. Among these molecules, a main role is occupied bythe TAM family of receptor tyrosine kinases, which isformed by three members, i.e., Tyro3, AxI, and Mer, thathave two vitamin K-dependent ligands, i.e., the growtharrest-specific protein (Gas)6 and Protein S [3]. In theSeptember 2013 issue of Intensive Care Medicine, Gui-gnant et al. [4] explored by an elegant experimental studythe expression of TAM receptors in circulating immunecells in patients with septic shock and after trauma, and inhealthy volunteers. A significant early alteration of MerTKexpression on monocytes and neutrophils was observed inpatients with septic shock, and a persistent MerTK over-expression after septic shock was associated with adverseoutcome. The ex vivo analysis showed also a differentMerTK surface expression of healthy monocytes after48 h incubation with plasma from septic or traumapatients, supporting the difference in TAM expressionbetween infection-induced inflammation and sterileinflammation (i.e., trauma). The study provides newimportant data on the mechanisms of immune response insepsis, but the true reasons for the observed alterations inMerKT expression and their role in the complex patho-physiological context of sepsis remain to be clarified.TAM receptors are under the control of Toll-likereceptors (TLR), and are widely expressed by cells of theinnateimmunesystem[5].ActivationofTAMreceptorsbytheir ligands triggers a cascade of intracellular events thatculminate in the inhibition of nuclear factor-kappaB (NF-jB), a crucial proinflammatory molecule, and results indownregulation of inflammation [6]. When expressed bymonocytes and granulocytes, these receptors (and in par-ticular MerTK) can also mediate the phagocytosis ofapoptoticcells[7],whichisfundamentalinordertoremovedead cells without triggering inflammation. Several datanow exist that underline the importance of MerTK activa-tion in the elimination of potential autoantigens derived byapoptotic cells, in the inhibition of the production of pro-inflammatory cytokines, and in the prevention of theexpansion of autoreactive lymphocytes [8–10]. The func-tional impairment of MerTK promotes not onlyautoimmunity but also atherosclerosis, while its overex-pression is linked to poor prognosis in cancer [11].The strong relationships existing between TAMreceptors and a proinflammatory molecule such as tumornecrosis factor-alpha (TNF-a) are reinforced by theobservation that they can interact with a common protein,the matrix metalloproteinase TNF-a converting enzyme,also known as ‘‘a disintegrin and a metalloproteinase 17’’(ADAM17). In order to provide the mature, soluble,secretable form of TNF-a, ADAM17 cleaves the mem-brane form of this important proinflammatory cytokine[12]. Interestingly, ADAM17 is also able to cleave the