Efferocytosis of SARS-CoV-2-infected dying cells impairs macrophage anti-inflammatory programming and continual clearance of apoptotic cells

AbstractCOVID-19 is a disease of dysfunctional immune responses, but the mechanisms triggering immunopathogenesis are not established. The functional plasticity of macrophages allows this cell type to promote pathogen elimination and inflammation or suppress inflammation and promote tissue remodeling and injury repair. During an infection, the clearance of dead and dying cells, a process named efferocytosis, can modulate the interplay between these contrasting functions. Here, we show that engulfment of SARS-CoV2-infected apoptotic cells (AC) exacerbates inflammatory cytokine production, inhibits the expression of efferocytic receptors, and impairs continual efferocytosis by macrophages. We also provide evidence that monocytes from severe COVID-19 patients express reduced levels of efferocytic receptors and fail to uptake AC. Our findings reveal that dysfunctional efferocytosis of SARS-CoV-2-infected cell corpses suppress macrophage anti-inflammation and efficient tissue repair programs and provide mechanistic insights for the pathogenesis of the hyperinflammation and extensive tissue damage associated with COVID-19.

Download Full-text

A8.28 Reconstituted high density lipoprotein (RHDL) modulates TH1 and TH17 immune responses and pro-inflammatory cytokine production in a murine model of rheumatoid arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2013-205124.202 ◽

2014 ◽

Vol 73 (Suppl 1) ◽

pp. A87.1-A87 ◽

Cited By ~ 1

Author(s):

I Tiniakou ◽

V I Zannis ◽

D Boumpas ◽

P Verginis ◽

D Kardassis

Keyword(s):

Rheumatoid Arthritis ◽

Immune Responses ◽

High Density Lipoprotein ◽

Murine Model ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Density Lipoprotein ◽

High Density ◽

Inflammatory Cytokine Production

Download Full-text

Apoptosis in the lung: induction, clearance and detection

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00320.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. L601-L611 ◽

Cited By ~ 65

Author(s):

P. M. Henson ◽

R. M. Tuder

Keyword(s):

Cell Death ◽

Tissue Repair ◽

Alternative Explanation ◽

Apoptotic Cell ◽

Lung Cells ◽

Apoptotic Cells ◽

Local Responses ◽

Apoptotic Cell Clearance ◽

Cell Clearance ◽

Dying Cells

Apoptosis and other forms of programmed cell death are important contributors to lung pathophysiology. In this brief review, we discuss some of the implications of finding apoptotic cells in the lung and methods for their detection. The balance between induction of apoptosis and the normally highly efficient clearance of such cells shows that these are highly dynamic processes and suggests that abnormalities of apoptotic cell clearance may be an alternative explanation for their detection. Because recognition of apoptotic cells by other lung cells has additional effects on inflammation, immunity, and tissue repair, local responses to the dying cells may also have important consequences in addition to the cell death itself.

Download Full-text

Differential effects of lactobacilli on activation and maturation of mouse dendritic cells

Beneficial Microbes ◽

10.3920/bm2013.0066 ◽

2014 ◽

Vol 5 (3) ◽

pp. 323-334 ◽

Cited By ~ 10

Author(s):

I. Elawadli ◽

J.T. Brisbin ◽

B.A. Mallard ◽

M.W. Griffiths ◽

M. Corredig ◽

...

Keyword(s):

Dendritic Cells ◽

Lactic Acid ◽

Lactic Acid Bacteria ◽

Immune Responses ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Lactobacillus Helveticus ◽

Inflammatory Cytokine Production

Lactic acid bacteria (LAB) are of interest because of their potential to modulate immune responses. The effects of LAB range from regulation to stimulation of the immune system. A series of studies were performed in vitro to study the effects of six lactic acid bacteria (LAB), Lactobacillus helveticus LH-2, Lactobacillus acidophilus La-5, La-115, La-116 and La-14, and Lactobacillus salivarius, on maturation and activation of mouse dendritic cells. Production of tumour necrosis factor (TNF)-?, interleukin (IL)-6 and IL-10 by dendritic cells (DCs) was determined after treating cells with live LAB. The expression of DC maturation markers, CD80 and CD40, was also measured using flow cytometry after stimulation with LAB. In addition, the expression of Toll-like receptors (TLRs) 2, 4 and 9 by DCs stimulated with LAB was measured. Our results revealed that LAB act differentially on pro-inflammatory and anti-inflammatory cytokine production and induction of co-stimulatory molecules by DCs. Specifically, L. salivarius was found to be the most effective LAB to induce pro-inflammatory cytokine production and expression of co-stimulatory molecules. Moreover, La-14, La-116 and La-5 induced moderate maturation and activation of DCs. On the other hand, LH-2 and La-115 were the least effective lactobacilli to induce DC responses. The present study also revealed that L. salivarius was able to induce the expression of TLR2, 4 and 9 by DCs. In conclusion, various strains and species of LAB can differentially regulate DC activation and maturation, providing further evidence that these bacteria may have the ability to influence and steer immune responses in vivo.

Download Full-text

Lipid Nanoparticle Acts as a Potential Adjuvant for Influenza Split Vaccine without Inducing Inflammatory Responses

Vaccines ◽

10.3390/vaccines8030433 ◽

2020 ◽

Vol 8 (3) ◽

pp. 433

Author(s):

Seiki Shirai ◽

Atsushi Kawai ◽

Meito Shibuya ◽

Lisa Munakata ◽

Daiki Omata ◽

...

Keyword(s):

Immune Responses ◽

Cytokine Production ◽

Immune Cell ◽

Inflammatory Responses ◽

Influenza Viruses ◽

Inflammatory Cytokine Production ◽

Virus Challenge ◽

Aluminum Salts ◽

Lipid Nanoparticle

Vaccination is a critical and reliable strategy for controlling the spread of influenza viruses in populations. Conventional seasonal split vaccines (SVs) for influenza evoke weaker immune responses than other types of vaccines, such as inactivated whole-virion vaccines, although SVs are highly safe compared to other types. Here, we assessed the potential of the lipid nanoparticle (LNP) we developed as an adjuvant for conventional influenza SV as an antigen in mice. The LNP did not induce the production of cytokines such as interleukin-6 (IL-6) and IL-12 p40 by dendritic cells or the expression of co-stimulatory molecules on these cells in vitro. In contrast, an SV adjuvanted with LNP improved SV-specific IgG1 and IgG2 responses and the Th1 response compared to the SV alone in mice. In addition, SV adjuvanted with an LNP gave superior protection against the influenza virus challenge over the SV alone and was as effective as SV adjuvanted with aluminum salts in mice. The LNP did not provoke inflammatory responses such as inflammatory cytokine production and inflammatory immune cell infiltration in mice, whereas aluminum salts induced inflammatory responses. These results suggest the potential of the LNP as an adjuvant without inflammatory responses for influenza SVs. Our strategy should be useful for developing influenza vaccines with enhanced efficacy and safety.

Download Full-text

Immunostimulatory Effect of Zanthoxylum schinifolium-Based Complex Oil Prepared by Supercritical Fluid Extraction in Splenocytes and Cyclophosphamide-Induced Immunosuppressed Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/8107326 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Hak Yong Lee ◽

Young Mi Park ◽

Yang Hee Lee ◽

Yang Gyu Kang ◽

Hyang Man Lee ◽

...

Keyword(s):

Immune Responses ◽

Cytokine Production ◽

Nk Cell ◽

Cell Activity ◽

Pharmacological Activities ◽

Inflammatory Cytokine Production ◽

Immunostimulatory Effect ◽

Zanthoxylum Schinifolium

Complex oil of Zanthoxylum schinifolium and Perilla frutescens seed (ZPCO) is used as a traditional medicine due to its pharmacological activities. The aim of this study was to investigate the immunostimulatory effect of ZPCO in isolated splenocytes as well as in an immunosuppressed rat model, which was generated via oral administration of cyclophosphamide. Notably, our results showed that ZPCO exerted an immunity-enhancing effect both in vitro and in vivo. Specifically, ZPCO treatment enhanced the viability and inflammatory cytokine production of splenocytes and NK cell activity in vitro. Moreover, this product improved host defense under immunosuppressive conditions by increasing the number of immune cells and promoting the expression of cytokines involved in immune responses. Our results suggest that complex oil including Z. schinifolium should be explored as a novel immunostimulatory agent that could potentially be used for therapeutic purposes or as an ingredient in functional foods.

Download Full-text

55 The effect of n-3 polyunsaturated fatty acids (DHA) and prebiotic supplementation on inflammatory cytokine production and immune responses to vaccination in old horses

Journal of Equine Veterinary Science ◽

10.1016/j.jevs.2015.03.065 ◽

2015 ◽

Vol 35 (5) ◽

pp. 407-408 ◽

Cited By ~ 2

Author(s):

A.A. Adams ◽

K.R. Vineyard ◽

M.E. Gordon ◽

S. Reedy ◽

M.H. Siard ◽

...

Keyword(s):

Fatty Acids ◽

Immune Responses ◽

Polyunsaturated Fatty Acids ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Inflammatory Cytokine Production

Download Full-text

Diazepam Impairs Innate and Adaptive Immune Responses and Ameliorates Experimental Autoimmune Encephalomyelitis

Frontiers in Immunology ◽

10.3389/fimmu.2021.682612 ◽

2021 ◽

Vol 12 ◽

Author(s):

Cristian R. Falcón ◽

Nicolás Fernández Hurst ◽

Ana Laura Vivinetto ◽

Pablo Héctor Horacio López ◽

Adolfo Zurita ◽

...

Keyword(s):

Immune Responses ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Clinical Signs ◽

Autoimmune Encephalomyelitis ◽

Adaptive Immune Responses ◽

Inflammatory Cytokine Production ◽

Adaptive Immune ◽

Experimental Autoimmune

Currently there is increasing attention on the modulatory effects of benzodiazepines on the immune system. Here, we evaluate how Diazepam (DZ) affects both innate and adaptive immunity. We observed that treatment with DZ and Lipopolysaccharide (LPS) on macrophages or dendritic cells (DCs) induced a defective secretion of IL-12, TNF-α, IL-6 and a lesser expression of classical activation markers as NO production and CD40 in comparison with LPS condition. More importantly, mice pre-treated with DZ and then challenged to LPS induced-septic shock showed reduced death. The DZ treatment shifted the LPS-induced pro-inflammatory cytokine production of peritoneal cells (PCs) to an anti-inflammatory profile commanded by IL-10. In agreement with this, DZ treatment prevented LPS-induced DC ability to initiate allogeneic Th1 and Th17 responses in vitro when compared with LPS-matured DC. Since these inflammatory responses are the key in the development of the experimental autoimmune encephalomyelitis (EAE), we treated EAE mice preventively with DZ. Mice that received DZ showed amelioration of clinical signs and immunological parameters of the disease. Additionally, DZ reduced the release of IFN-γ and IL-17 by splenocytes from untreated sick mice in vitro. For this reason, we decided to treat diseased mice therapeutically with DZ when they reached the clinical score of 1. Most importantly, this treatment ameliorated clinical signs, reduced the MOG-specific inflammatory cytokine production and prevented axonal damage. Altogether, these results indicate that DZ is a potent immunomodulator capable of controlling undesired innate and adaptive immune responses, both at the beginning of these responses and also once they have started.

Download Full-text