Thymosin α₁ Activates Complement Receptor-Mediated Phagocytosis in Human Monocyte-Derived Macrophages

Abstract

Thymosin α₁ (Tα1) is a naturally occurring thymic peptide used worldwide in clinical trials for the treatment of infectious diseases and cancer. The immunomodulatory activity of Tα1 on innate immunity effector cells has been extensively described, but its mechanism of action is not completely understood. We report that Tα1-exposed human monocyte-derived macrophages (MDMs) assume the typical activated morphology also exhibited by lipopolysaccharide-activated MDMs, but show a comparatively higher ability of internalizing fluorescent beads and zymosan particles. Tα1 exposure also promptly and dramatically stimulates MDM phagocytosis and killing of Aspergillus niger conidia starting as soon as 30 min after challenge. The effect is dose dependent and early coupled to low transcription of the proinflammatory cytokines tumor necrosis factor α and interleukin-6 and unmodified Toll-like receptor expression. The Tα1-stimulated phagocytosis is strictly dependent on the integrity of the microtubule network and protein kinase C activity and occurs by a variation in the classic zipper model, with recruitment of vinculin and actin at the phagosome exhibiting a punctate distribution. These findings indicate that, in human mature MDMs, Tα1 implements pathogen internalization and killing via the stimulation of the complement receptor-mediated phagocytosis. Our observations document that Tα1 is an early and potent activator of innate immunity and reinforce the concept of its pleiotropy.

Thymosin α1 Interacts with Hyaluronic Acid Electrostatically by Its Terminal Sequence LKEKK

“…These findings are in agreement with a growing body of evidence attesting the pleiotropy of this hormone peptide, which targets both normal and tumor cells interacting with multiple cellular components [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]; as such, they have generated a renewed interest. Studies of the serum Tα1 levels and of its interaction with soluble proteins [ 23 , 29 ] have also raised questions about the transport and localization of Tα1 in tissues and of the dynamics underlying the biological effects of this peptide in different clinical situations.…”

“…A univocal mechanism of action of Tα1 is still unknown since no specific receptors for Tα1 have been identified. Tα1 induces T-cell and dendritic cell (DC) maturation and interleukin (IL)-2 expression; it is also capable of upregulating the expression of some Toll-like receptors (TLRs) in murine DCs protecting mice from invasive aspergillosis in the MyD88 (myeloid differentiate factor 88)-dependent way [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Tα1 activates a protein kinase C (PKC)-IκB kinase (TRAF6) that is an atypical signaling pathway activating nuclear factor-κB and initiating the cytokine gene expression in murine bone marrow-derived macrophages [ 21 ].…”

Foodies of Innate Immunity

“…Macrophages can regulate inflammation, but a janitorial function is also important, for example, the removal of apoptotic cells (efferocytosis) [9][10][11] . In this context, autophagy, involving the recycling of cells and debris, plays a critical role [12][13][14][15] .…”

On PAMPs and DAMPs

“…It will be interesting to see whether this finding has clinical implications. For instance, Annalucia Serafino and colleagues recently reported that thymosin α 1 can boost complement receptor-mediated phagocytosis by activating a TRAF6-atypical protein kinase C-IκB kinase signaling pathway [18]. Notably, many of these signaling events involve an activation of Pyk kinases.…”