Training vs. Tolerance: The Yin/Yang of the Innate Immune System

ORCID
0000-0002-2584-589X
Affiliation
Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
Lajqi, Trim;
ORCID
0000-0003-3718-5507
Affiliation
Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
Köstlin-Gille, Natascha;
GND
120228920
ORCID
0000-0002-4294-3758
Affiliation
Institute of Molecular Cell Biology, Jena University Hospital, D-07745 Jena, Germany
Bauer, Reinhard;
ORCID
0000-0002-3083-3244
Affiliation
Department of Physiology, School of Health Sciences, Faculty of Medicine, University of Thessaly, GR-41500 Larissa, Greece
Zarogiannis, Sotirios G.;
Affiliation
Department of Radiation Oncology, Heidelberg University Hospital, D-69120 Heidelberg, Germany
Lajqi, Esra;
Affiliation
Department of Pharmacy, Alma Mater Europaea—Campus College Rezonanca, XK-10000 Pristina, Kosovo
Ajeti, Valdrina;
Affiliation
Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
Dietz, Stefanie;
Affiliation
Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
Kranig, Simon A.;
Affiliation
Department of Neonatology, University of Tübingen, D-72076 Tübingen, Germany
Rühle, Jessica;
Affiliation
Faculty of Medical Sciences, University of Tetovo, MK-1200 Tetova, North Macedonia
Demaj, Ardian;
ORCID
0000-0003-1679-4418
Affiliation
Department of Neonatology, University of Tübingen, D-72076 Tübingen, Germany
Hebel, Janine;
ORCID
0000-0003-1127-3453
Affiliation
Center for Pediatric and Adolescent Medicine Heidelberg, University of Heidelberg, D-69120 Heidelberg, Germany
Bartosova, Maria;
Affiliation
Klinik für Kinderheilkunde und Jugendmedizin, D-87700 Memmingen, Germany
Frommhold, David;
Affiliation
Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
Hudalla, Hannes;
Affiliation
Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
Gille, Christian

For almost nearly a century, memory functions have been attributed only to acquired immune cells. Lately, this paradigm has been challenged by an increasing number of studies revealing that innate immune cells are capable of exhibiting memory-like features resulting in increased responsiveness to subsequent challenges, a process known as trained immunity (known also as innate memory). In contrast, the refractory state of endotoxin tolerance has been defined as an immunosuppressive state of myeloid cells portrayed by a significant reduction in the inflammatory capacity. Both training as well tolerance as adaptive features are reported to be accompanied by epigenetic and metabolic alterations occurring in cells. While training conveys proper protection against secondary infections, the induction of endotoxin tolerance promotes repairing mechanisms in the cells. Consequently, the inappropriate induction of these adaptive cues may trigger maladaptive effects, promoting an increased susceptibility to secondary infections—tolerance, or contribute to the progression of the inflammatory disorder—trained immunity. This review aims at the discussion of these opposing manners of innate immune and non-immune cells, describing the molecular, metabolic and epigenetic mechanisms involved and interpreting the clinical implications in various inflammatory pathologies.

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