It is the major aim of this preclinical project to investigate and understand the mechanisms underlying the development of splenic ex vivo glucocorticoid (GC) resistance in male mice as consequence of psychosocial stress associated with physical trauma, as for instance severe bite wounds or planned surgery.

Background: Chronic psychosocial stress is a major burden of modern life and poses an acknowledged risk factor for many somatic and psychiatric disorders, which are often associated with chronic low-grade inflammation.(1-8) Many clinical and preclinical studies(6, 9-14) support the hypothesis that stress-associated inflammation is promoted at least in part via development of glucocorticoid (GC) resistance, defined as a state of reduced sensitivity to the anti-inflammatory action of GCs, in certain immune cell subpopulations(6, 11) amongst which myeloid CD11b+ cells seem to play a critical role.(12, 13, 15) Noteworthy, over-shooting local and/ or systemic inflammatory responses(16-22) as well as development of GC resistance(23-25) further promote posttraumatic complications (e.g., septic shock), for patients on intensive care.

Therefore, a history of chronic/traumatic psychosocial stress and the subsequent development of GC resistance is a plausible scenario in vulnerable subgroups of physical trauma patients on intensive care. Of note, MDSCs represent immature myeloid cells, are generated in the bone marrow and able to suppress T cell proliferation via generation of nitric oxide (NO) and reactive oxygen species, as well as via depletion of arginine and down-regulation of the T cell receptor complex ζ chain, and have been first described in tumor patients and tumor-bearing mice.(26-28) As MDSCs are also induced during bacterial infections,(29, 30) they seem to provide a cellular link between activation of innate immunity and concomitant suppression of adaptive immunity.

Main findings: In a series of preclinical experiments employing the chronic subordinate colony housing (CSC) paradigm as an acknowledged model for social stress-associated posttraumatic stress disorder (PTSD) in male mice(31, 32) we could show that particularly CD11b+Ly6G+Ly6C+ polymorphonuclear (PMN)-myeloid-derived suppressor cells (MDSCs) play a critical role in psychosocial stress-induced splenic ex vivo functional GC resistance.(33-36) In detail, we showed that CSC accompanied by significant wounding and, thus, a combination of psychosocial and physical trauma, i) enhanced basal and LPS-induced ex vivo cell viability of isolated BM cells, ii) increased the percentage of toll-like receptor (TLR)2-expressing bone marrow (BM) and spleen CD11b+Ly6G+Ly6C- neutrophils, PMN-MDSCs and CD11b+Ly6G-Ly6C+ monocytes/MO-MDSCs, iii) increased the percentage of TLR4-expressing spleen PMN-MDSCs and monocytes/ mononuclear (MO)-MDSCs, iv) enhanced basal and LPS-induced ex vivo cell viability of isolated PMN-MDSC-enriched PBMCs and splenocytes, as well as ex vivo migration activity of neutrophil/PMN-MDSC-enriched WBCs, v) induced ex vivo GC resistance in LPS-stimulated Ly6G+ splenocytes but not Ly6G-depleted total splenocytes or PMN-MDSC-enriched PBMCs, vi) rendered stress-induced Ly6G+ splenocytes to increase cell viability upon LPS stimulation exclusively via the NF-κB pathway.(37) These results support the hypothesis that stress-induced PMN-MDSCs get primed(37) and activated locally in the bone marrow (BM) as determined by toll-like receptor (TLR)2 and TH, but not TLR4, upregulation and increased basal and lipopolysaccharide (LPS)-induced ex vivo cell viability.(33) These primed and activated PMN-MDSCs emigrate into the peripheral circulation and subsequently, if psychosocial stress is accompanied by significant bite wounding, accumulate in the spleen(33). In the spleen, PMN-MDSCs upregulate TLR4 expression, which in concert with PMN-MDSCs-derived catecholamines as a consequence of increased TH expression promotes NF-κB hyperactivation upon LPS-stimulation, thereby exceeding the anti-inflammatory capacities of GCs and resulting in GC resistance.(33) Upregulation of myeloid-derived catecholamines as a consequence of TH upregulation has been shown to promote NF-κB signaling and to augment the acute inflammatory response to acute lung injury.(38, 39).

Main collaborators: Prof. Dr. Jan Tuckermann & Prof. Dr. Maja Vujić Spasić (Ulm University, Ulm, Germany), Prof. Dr. Steffen Stenger (Ulm University Medical Center, Ulm, Germany).

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