Human monocytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1α.
Sepsis is characterized by a dysregulated inflammatory response to infection. Despite studies in mice, the cellular and molecular basis of human sepsis remains unclear and effective therapies are lacking. Blood monocytes serve as the first line of host defense and are equipped to recognize and respond to infection by triggering an immune-inflammatory response. However, the response of these cells in human sepsis and their contribution to sepsis pathogenesis is poorly understood. To investigate this, we performed a transcriptomic, functional, and mechanistic analysis of blood monocytes from patients during sepsis and after recovery. Our results revealed the functional plasticity of monocytes during human sepsis, wherein they transited from a pro-inflammatory to an immunosuppressive phenotype, while enhancing protective functions like phagocytosis, anti-microbial activity, and tissue remodeling. Mechanistically, hypoxia inducible factor-1α (HIF1α) mediated this functional re-programming of monocytes, revealing a potential mechanism for their therapeutic targeting to regulate human sepsis.
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, #04-06 Immunos building, 8A Biomedical Grove, Singapore 138648, Singapore.
Irina N
IN
Shalova
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, #04-06 Immunos building, 8A Biomedical Grove, Singapore 138648, Singapore.
Jyue Yuan
JY
Lim
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, #04-06 Immunos building, 8A Biomedical Grove, Singapore 138648, Singapore.
Manesh
M
Chittezhath
Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Annelies S
AS
Zinkernagel
Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Federico
F
Beasley
Tumor Immunology Lab and Innate Immunity Group, IdiPAZ, "La Paz" Hospital, Pseo de La Castellana 261, Madrid 28046, Spain.
Enrique
E
Hernández-Jiménez
Tumor Immunology Lab and Innate Immunity Group, IdiPAZ, "La Paz" Hospital, Pseo de La Castellana 261, Madrid 28046, Spain.
Victor
V
Toledano
Tumor Immunology Lab and Innate Immunity Group, IdiPAZ, "La Paz" Hospital, Pseo de La Castellana 261, Madrid 28046, Spain.
Carolina
C
Cubillos-Zapata
Development Therapeutic Program, Tumor Hypoxia Laboratory, Science Applications International Corporation-Frederick, Inc., National Cancer Institute, Frederick, MD 21701, USA.
Annamaria
A
Rapisarda
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, #04-06 Immunos building, 8A Biomedical Grove, Singapore 138648, Singapore.
Jinmiao
J
Chen
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, #04-06 Immunos building, 8A Biomedical Grove, Singapore 138648, Singapore.
Kaibo
K
Duan
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, #04-06 Immunos building, 8A Biomedical Grove, Singapore 138648, Singapore.
Henry
H
Yang
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, #04-06 Immunos building, 8A Biomedical Grove, Singapore 138648, Singapore.
Michael
M
Poidinger
Development Therapeutic Program, Tumor Hypoxia Laboratory, Science Applications International Corporation-Frederick, Inc., National Cancer Institute, Frederick, MD 21701, USA.
Giovanni
G
Melillo
Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Victor
V
Nizet
Department of Internal Medicine, "La Paz" Hospital, Pseo de La Castellana 261, Madrid 28046, Spain.
Francisco
F
Arnalich
Tumor Immunology Lab and Innate Immunity Group, IdiPAZ, "La Paz" Hospital, Pseo de La Castellana 261, Madrid 28046, Spain.
Eduardo
E
López-Collazo
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, #04-06 Immunos building, 8A Biomedical Grove, Singapore 138648, Singapore. Electronic address: subhra_biswas@immunol.a-star.edu.sg.
Subhra K
SK
Biswas
D056704:Adaptive Immunity; D065150:Cellular Reprogramming / Q000276:immunology*; D003289:Convalescence; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate; D016867:Immunocompromised Host; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology*; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D010587:Phagocytosis; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D059467:Transcriptome / Q000276:immunology
D016207:Cytokines; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases