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Nat Immunol ; 23(1): 62-74, 2022 01.
Article in English | MEDLINE | ID: covidwho-1514418


The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.

Interferon-gamma/immunology , Interleukin-10/immunology , SARS-CoV-2/immunology , Th1 Cells/immunology , Vitamin D/metabolism , 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/metabolism , Basic-Leucine Zipper Transcription Factors/metabolism , Bronchoalveolar Lavage Fluid/cytology , COVID-19/immunology , COVID-19/pathology , Complement C3a/immunology , Complement C3b/immunology , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Lymphocyte Activation/immunology , Receptors, Calcitriol/metabolism , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , STAT3 Transcription Factor/metabolism , Signal Transduction/immunology , Transcription, Genetic/genetics
Int J Mol Sci ; 22(11)2021 May 24.
Article in English | MEDLINE | ID: covidwho-1273453


Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. Lipopolysaccharide (LPS) is usually used intratracheally to induce ALI in mice. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (um-PEA) in mice subjected to LPS-induced ALI. Histopathological analysis reveals that um-PEA reduced alteration in lung after LPS intratracheal administration. Besides, um-PEA decreased wet/dry weight ratio and myeloperoxidase, a marker of neutrophils infiltration, macrophages and total immune cells number and mast cells degranulation in lung. Moreover, um-PEA could also decrease cytokines release of interleukin (IL)-6, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and interleukin (IL)-18. Furthermore, um-PEA significantly inhibited the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in ALI, and at the same time decreased extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38/MAPK) expression, that was increased after LPS administration. Our study suggested that um-PEA contrasted LPS-induced ALI, exerting its potential role as an adjuvant anti-inflammatory therapeutic for treating lung injury, maybe also by p38/NF-κB pathway.

Acute Lung Injury/drug therapy , Amides/pharmacology , Cytokines/metabolism , Ethanolamines/pharmacology , MAP Kinase Signaling System/drug effects , Palmitic Acids/pharmacology , Acute Lung Injury/metabolism , Acute Lung Injury/pathology , Amides/therapeutic use , Animals , Ethanolamines/therapeutic use , Immunohistochemistry , Inflammation/metabolism , Interleukin-18/metabolism , Interleukin-1beta/metabolism , Interleukin-6/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Lipopolysaccharides/administration & dosage , Lipopolysaccharides/toxicity , Macrophages/drug effects , Macrophages/immunology , Male , Mast Cells/drug effects , Mast Cells/pathology , Mice , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , NF-KappaB Inhibitor alpha/metabolism , NF-kappa B/metabolism , Neutrophils/drug effects , Neutrophils/immunology , Palmitic Acids/therapeutic use , Peroxidase/metabolism , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
Adv Chronic Kidney Dis ; 27(5): 404-411, 2020 09.
Article in English | MEDLINE | ID: covidwho-722379


Hypertension emerged from early reports as a potential risk factor for worse outcomes for persons with coronavirus disease 2019 (COVID-19). Among the putative links between hypertension and COVID-19 is a key counter-regulatory component of the renin-angiotensin system (RAS): angiotensin-converting enzyme 2 (ACE2). ACE2 facilitates entry of severe acute respiratory syndrome coronavirus 2, the virus responsible for COVID-19, into host cells. Because RAS inhibitors have been suggested to increase ACE2 expression, health-care providers and patients have grappled with the decision of whether to discontinue these medications during the COVID-19 pandemic. However, experimental models of analogous viral pneumonias suggest RAS inhibitors may exert protective effects against acute lung injury. We review how RAS and ACE2 biology may affect outcomes in COVID-19 through pulmonary and other systemic effects. In addition, we briefly detail the data for and against continuation of RAS inhibitors in persons with COVID-19 and summarize the current consensus recommendations from select specialty organizations.

Acute Lung Injury/metabolism , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/metabolism , Hypertension/drug therapy , Acute Lung Injury/epidemiology , Acute Lung Injury/immunology , Angiotensin I/immunology , Angiotensin I/metabolism , Angiotensin II/immunology , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/immunology , COVID-19/epidemiology , COVID-19/immunology , Comorbidity , Humans , Hypertension/epidemiology , Hypertension/metabolism , JNK Mitogen-Activated Protein Kinases/immunology , JNK Mitogen-Activated Protein Kinases/metabolism , Lung/immunology , Lung/metabolism , MAP Kinase Signaling System , Peptide Fragments/immunology , Peptide Fragments/metabolism , Protective Factors , Receptors, Coronavirus/immunology , Receptors, Coronavirus/metabolism , Renin-Angiotensin System , Risk Factors , SARS-CoV-2 , Up-Regulation