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Figure 1. Signals involved in apoptotic cell removal. Different signals orchestrate apoptotic cell removal by neighbor cells (amateur phagocytes; see Table 1 ) or professional phagocytes, such as macrophages or conventional dedritic cells. These signals include: (A) the loss of 'do-not-eat-me'signals; (B) the secretion of 'find-me'signals that can be counterbalanced by 'keep-out'signals [133] ; and (C) the acquisition of 'eat-me'signals that are similar between (i) amateur and (ii) professional phagocytes. Soluble factors can participate in accelerated elimination of apoptotic cells. CRT: Calreticulin; PS: Phosphatidylserine; TSP1: Thrombospondin 1. Adapted with permission from [134].
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Figure 2. Immunomodulatory microenvironment created by apoptotic cells. During the apoptotic process, apoptotic cells can spontaneously produce anti-inflammatory factors, such as IL-10 [44] or TGF-β [43] , or be a source of CCR5 chemokine receptor that neutralizes its ligands, CCL3/MIP-1αor CCL5/RANTES, and subsequently blocks immune cell migration [42]. Apoptotic cells interact with several innate immune cells or APCs, including monocytes, Mφ, microglia in the brain, cDCs, NK cells or B cells. Uptake of apoptotic cells or only the interaction with apoptotic cells lead to modulation of several factors in innate cells or APCs. These factors are mentioned in boxes linked to each APC or innate cell subset. Some of these factors are spontaneously produced after apoptotic cell encounter or increased or diminished after a subsequent stimulation by Toll-like receptor ligands in the context of inflammation (Table 1). Concerning NO synthesis, differences exist between human and mouse macrophages [135] and maybe also between in vivo and in vitro conditions [136]. [arrow down]: Decrease; [arrow up]: Increase; AhR: Aryl hydrocarbon receptor; cDC: Conventional dendritic cell; IL-1RA: IL-1 receptor antagonist; iNOS: Inducible nitric oxide synthase; LTC4: Leukotriene C4; Mφ: Macrophage; NO: Nitric oxide; NOS2: Nitric oxide synthase 2; PGE-2: Prostaglandin-E2; pTreg: Peripherally derived Foxp3+ CD4+ Treg; RvE: Resolvin E; Th0: Uncommitted naive T cell; TXA2: Thromboxane A2. Adapted with permission from [137].
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Figure 3. Anti-inflammatory effects versus tolerance induction after early apoptotic cell infusion. Apoptotic cell-induced immunosuppression is transient (limited to the timecourse of apoptotic cell removal and the persistence of immunosuppressive cytokines: mainly IL-10 and TGF-β; see also Figure 2 ), localized to the site where the cells are dying and/or being...