Endogenous glucocorticoids control neutrophil mobilization from bone marrow to blood and tissues in non‐inflammatory conditions

Abstract

Background and purpose: We have shown that endogenous glucocorticoids control neutrophil mobilization in the absence of inflammation. In this study the role of the glucocorticoid receptor (GR) in the physiological control of neutrophil mobilization was investigated, focusing on the specific mechanisms for mature neutrophils in bone marrow, circulating neutrophils and endothelial cells. Experimental approach: Male Wistar rats were treated with RU 38486 or adrenalectomized. Cell numbers in bone marrow and circulation were morphologically quantified and expressions of L-selectin determined by flow cytometry. Expressions of Pselectin, E-selectin, PECAM-1, VCAM-1 and ICAM-1 were measured by immunohistochemistry on vessels of cremaster muscle and their mRNA levels quantified in primary cultured endothelial cells. NF-kB activity in neutrophils and endothelium was quantified by EMSA. Key results: RU 38486 treatment altered the maturation phases of neutrophilic lineage and reduced expression of L-selectin in mature neutrophils from bone marrow; increased the number of neutrophils in the circulation and elevated the expression of L-selectin in these cells. P-selectin and E-selectin expression in endothelial cells was unchanged by adrenalectomy or RU 38486 treatment. Membrane expressions, mRNA levels of ICAM-1, VCAM-1 and PECAM-1 and NF-kB translocation into the nucleus were higher in the endothelium of adrenalectomized and RU 38486 treated rats. Conclusions and implications: Endogenous glucocorticoids, through activation of GR on neutrophils, physiologically control the rolling behaviour of these cells and, by modulating endothelial functions, affect their adhesiveness. The molecular mechanism induced by activated GR is different in each cell, as NF-kB translocation was only altered in endothelial cells.

Mecanismos moleculares da ação dos glicocorticóides endógenos e da anexina-A1 sobre o tráfego de neutrófilos: caracterização da ação sobre os eixos SDF-1α/CXCR4 e IL-17/IL-23/G-CSF

“…The same pattern of leukocyte trafficking is induced by high concentrations of synthetic glucocorticoid or by injection of adrenocorticotropic hormone (ACTH) [20,21]. Interestingly, in the absence of stress conditions, neutrophilia has also been detected in animals deficient in glucocorticoid activity [22,23], indicating the existence of a tight physiological control on neutrophil trafficking by secreted glucocorticoids.…”

“…Therefore, the molecular interactions of bone marrow granulocytes, stromal cells, sinusoids and microvessels are under the control of chemical mediators of stress [37,38,39,40]. We and others have shown that secreted or exogenous glucocorticoids modulate both physiological and stress-mediated granulopoiesis and bone marrow granulocyte delivery [23,33,41]. Here we show that AnxA1, a protein secreted in response to glucocorticoid action, controls granulopoiesis and bone marrow/blood/bone marrow trafficking by modulating granulocyte maturation phases and the CXCR4/SDF-1α…”

“…We had previously demonstrated that an absence of circulating glucocorticoids, or blockade of glucocorticoid receptors, affects the production, maturation and delivery of granulocytes from the bone marrow, as visualized by the greater numbers of blast, immature and band cells accompanying blood neutrophilia in rats [23]. Morphological and flow cytometric analysis carried out in the present manuscript showed that the actions of secreted glucocorticoids on maturation and delivery, but not on the production of granulocytes, may involve AnxA1 secretion and its interaction with FPR2, in view of the findings produced with AnxA1 -/-, Ac2-26…”

Efeitos dos ligantes de TSPO sobre a migração leucocitária: participação de receptores de glicorticóides

“…Tem sido mostrado que os GE inibem a translocação nuclear do fator de transcrição NFkappa B na célula endotelial, que inibe a expressão gênica de imunoglobulinas (CAVALCANTI et. al., 2007) , e que a modulação sobre a L-selectina é dependente da anexina-1 (ANXA1), uma proteína antiinflamatória sintetizada pela ação dos GC (CAVALCANTI et. al., 2007;D'ACQUISTO,2009).…”

“…al., 1993;LIANG-SUO et. al., 2002;CAVALCANTI et. al., 2007;JURADO, 2009) e, assim, tem sido observado que sua meia-vida é superior a 24 horas e que o tratamento in vivo com RU 38486 exacerba os eventos da resposta inflamatória (LAUE et.…”