Regulation of dendritic cells and their progenitors in infectious diseases
Final Report Abstract
Upon the fight against invading pathogens mechanisms and events such as mobilization to the sites of infection or apoptosis lead to the consumption of immune cells. Dendritic cells (DCs) are key players of the adaptive immune response playing a crucial role in the initiation of T-cell responses to combat infection. However, systemic bacterial infection with various pathogens leads to DC-depletion in humans and mice. Therefore, the regulation of DCs and their progenitors upon infection/inflammation is an emerging field of interest in which the mechanisms of pathogen-induced DC-depletion remain poorly understood. Previously, we showed that mice infected with Yersinia enterocolitica (Ye) had impaired de novo DC-development, one reason for DC-depletion. Here, we extend these studies to gain insight into the molecular mechanisms of DC-depletion and the impact of different bacteria on DC development. Using the model pathogen Yersinia enterocolitica (Ye) in an experimental mouse infection model we showed that the number of bone marrow (BM) hematopoietic progenitors committed to the DC lineage is reduced following systemic infection with different Gram-positive and Gram-negative bacteria. This reduction is not due to cell death or migration of DC progenitors from the BM before differentiation, but rather to a biased differentiation of monocyte and DC progenitors (MDPs) into monocytes by increased expression of MafB. Infection-induced monopoiesis is TLR4- and IFN-gamma-signaling dependent and adoptive transfer experiments revealed that it occurs at the expense of DC-development. Interestingly, live but not dead bacteria actively inhibit the differentiation capacity of common DC progenitors (CDPs) into DCs by reprogramming them to differentiate into inflammatory monocyte-like cells. Our data provide evidence for a general response of hematopoietic progenitors upon systemic bacterial infections to enhance monocyte production, thereby increasing the availability of innate immune cells for pathogen control, whereas impaired DC-development leads to DC-depletion, possibly driving transient immunosuppression in bacterial sepsis.
Publications
- Innate immune system favors emergency monopoiesis at the expense of DC-differentiation to control systemic bacterial infection in mice. Eur J Immunol. 2015 Oct;45(10):2821-33
Pasquevich KA, Bieber K, Günter M, Grauer M, Pötz O, Schleicher U, Biedermann T, Beer-Hammer S, Bühring HJ, Rammensee HG, Zender L, Autenrieth IB, Lengerke C, Autenrieth SE
(See online at https://doi.org/10.1002/eji.201545530) - Insights how monocytes and dendritic cells contribute and regulate immune defense against microbial pathogens. Immunobiology. 2015 Feb;220(2):215-26
Bieber K, Autenrieth SE
(See online at https://doi.org/10.1016/j.imbio.2014.10.025) - 2016. Role of β1 integrins and bacterial adhesins for Yop injection into leukocytes in Yersinia enterocolitica systemic mouse infection. Int J Med Microbiol 306:77–88
Deuschle E, Keller B, Siegfried A, Manncke B, Spaeth T, Köberle M, Drechsler-Hake D, Reber J, Böttcher RT, Autenrieth SE, Autenrieth IB, Bohn E, Schütz M
(See online at https://doi.org/10.1016/j.ijmm.2015.12.001)
