Interleukin-4 receptor alpha signaling regulates monocyte homeostasis.

Autor: Haider P; Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria., Kral-Pointner JB; Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.; Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria., Salzmann M; Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria., Moik F; Division of Haematology and Haemostaseology, Comprehensive Cancer Center, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria., Bleichert S; Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria., Schrottmaier WC; Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, Vienna, Austria., Kaun C; Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria., Brekalo M; Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria., Fischer MB; Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria.; Department of Biomedical Research, Danube University Krems, Krems, Austria., Speidl WS; Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria., Hengstenberg C; Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria., Podesser BK; Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria.; Center for Biomedical Research, Medical University of Vienna, Vienna, Austria., Huber K; 3rd Department of Medicine, Cardiology and Intensive Care Medicine, Wilhelminenhospital, Vienna, Austria.; Medical Faculty, Sigmund Freud University, Vienna, Austria., Pabinger I; Division of Haematology and Haemostaseology, Comprehensive Cancer Center, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria., Knapp S; Laboratory of Infection Biology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria., Brombacher F; Institute of Infectious Disease and Molecular Medicine, International Center for Genetic and Biotechnology Cape Town Component & University of Cape Town, Cape Town, South Africa., Brostjan C; Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria., Ay C; Division of Haematology and Haemostaseology, Comprehensive Cancer Center, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria., Wojta J; Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.; Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria.; Core Facilities, Medical University of Vienna, Vienna, Austria., Hohensinner PJ; Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.; Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria.; Center for Biomedical Research, Medical University of Vienna, Vienna, Austria.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2022 Oct; Vol. 36 (10), pp. e22532.
DOI: 10.1096/fj.202101672RR
Abstrakt: Interleukin-4 (IL-4) and its receptors (IL-4R) promote the proliferation and polarization of macrophages. However, it is unknown if IL-4R also influences monocyte homeostasis and if steady state IL-4 levels are sufficient to affect monocytes. Employing full IL-4 receptor alpha knockout mice (IL-4Rα -/- ) and mice with a myeloid-specific deletion of IL-4Rα (IL-4Rα f/f LysM cre ), we show that IL-4 acts as a homeostatic factor regulating circulating monocyte numbers. In the absence of IL-4Rα, murine monocytes in blood were reduced by 50% without altering monocytopoiesis in the bone marrow. This reduction was accompanied by a decrease in monocyte-derived inflammatory cytokines in the plasma. RNA sequencing analysis and immunohistochemical staining of splenic monocytes revealed changes in mRNA and protein levels of anti-apoptotic factors including BIRC6 in IL-4Rα -/- knockout animals. Furthermore, assessment of monocyte lifespan in vivo measuring BrdU + cells revealed that the lifespan of circulating monocytes was reduced by 55% in IL-4Rα -/- mice, whereas subcutaneously applied IL-4 prolonged it by 75%. Treatment of human monocytes with IL-4 reduced the amount of dying monocytes in vitro. Furthermore, IL-4 stimulation reduced the phosphorylation of proteins involved in the apoptosis pathway, including the phosphorylation of the NFκBp65 protein. In a cohort of human patients, serum IL-4 levels were significantly associated with monocyte counts. In a sterile peritonitis model, reduced monocyte counts resulted in an attenuated recruitment of monocytes upon inflammatory stimulation in IL-4Rα f/f LysM cre mice without changes in overall migratory function. Thus, we identified a homeostatic role of IL-4Rα in regulating the lifespan of monocytes in vivo.
(© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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