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Immune Complex-Driven Generation of Human Macrophages with Anti-Inflammatory and Growth-Promoting Activity.

ABSTRACT: To maintain homeostasis, macrophages must be capable of assuming either an inflammatory or an anti-inflammatory phenotype. To better understand the latter, we stimulated human macrophages in vitro with TLR ligands in the presence of high-density immune complexes (IC). This combination of stimuli resulted in a broad suppression of inflammatory mediators and an upregulation of molecules involved in tissue remodeling and angiogenesis. Transcriptomic analysis of TLR stimulation in the presence of IC predicted the downstream activation of AKT and the inhibition of GSK3. Consequently, we pretreated LPS-stimulated human macrophages with small molecule inhibitors of GSK3 to partially phenocopy the regulatory effects of stimulation in the presence of IC. The upregulation of DC-STAMP and matrix metalloproteases was observed on these cells and may represent potential biomarkers for this regulatory activation state. To demonstrate the presence of these anti-inflammatory, growth-promoting macrophages in a human infectious disease, biopsies from patients with leprosy (Hanseniasis) were analyzed. The lepromatous form of this disease is characterized by hypergammaglobulinemia and defective cell-mediated immunity. Lesions in lepromatous leprosy contained macrophages with a regulatory phenotype expressing higher levels of DC-STAMP and lower levels of IL-12, relative to macrophages in tuberculoid leprosy lesions. Therefore, we propose that increased signaling by FcγR cross-linking on TLR-stimulated macrophages can paradoxically promote the resolution of inflammation and initiate processes critical to tissue growth and repair. It can also contribute to infectious disease progression.

SUBMITTER: Dalby E

PROVIDER: S-EPMC9358719 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Immune Complex-Driven Generation of Human Macrophages with Anti-Inflammatory and Growth-Promoting Activity.

Dalby Elizabeth E Christensen Stephen M SM Wang Jingya J Hamidzadeh Kajal K Chandrasekaran Prabha P Hughitt V Keith VK Tafuri Wagner Luiz WL Arantes Rosa Maria Esteves RME Rodrigues Ismael Alves IA Herbst Ronald R El-Sayed Najib M NM Sims Gary P GP Mosser David M DM

Journal of immunology (Baltimore, Md. : 1950) 20200520 1

To maintain homeostasis, macrophages must be capable of assuming either an inflammatory or an anti-inflammatory phenotype. To better understand the latter, we stimulated human macrophages in vitro with TLR ligands in the presence of high-density immune complexes (IC). This combination of stimuli resulted in a broad suppression of inflammatory mediators and an upregulation of molecules involved in tissue remodeling and angiogenesis. Transcriptomic analysis of TLR stimulation in the presence of IC ...[more]

PMID: 32434940

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Project description:Ethnopharmacological relevanceCaesalpinia sappan is a common remedy in Traditional Chinese Medicine and possesses diverse biological activities including anti-inflammatory properties. Osteoarthritis (OA) is a degenerative joint disease with an inflammatory component that drives the degradation of cartilage extracellular matrix. In order to provide a scientific basis for the applicability of Caesalpinia sappan in arthritic diseases, the present study aimed to assess the effects of an ethanolic Caesalpinia sappan extract (CSE) on human chondrocytes and macrophages.Materials and methodsPrimary human chondrocytes were isolated from cartilage specimens of OA patients. Primary cells, SW1353 chondrocytes and THP-1 macrophages were serum-starved and pretreated with different concentrations of CSE prior to stimulation with 10 ng/ml of interleukin-1beta (IL-1?) or lipopolysaccharide (LPS). Following viability tests, nitric oxide (NO) and tumor necrosis factor-alpha (TNF-?) were evaluated by Griess assay and ELISA, respectively. Using validated real-time PCR assays, mRNA levels of IL-1?, TNF-?, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were quantified. SW1353 cells were cotransfected with a COX-2 luciferase reporter plasmid and nuclear factor-kappa-B (NF-?B) p50 and p65 expression vectors in the presence or absence of CSE.ResultsCSE dose-dependently inhibited the expression of pro-inflammatory cytokines IL-1? and TNF-? in IL-1?-stimulated chondrocytes and LPS-stimulated THP-1 macrophages. CSE further suppressed the synthesis of NO in primary OA chondrocytes by blocking iNOS mRNA expression. The inhibition of COX-2 transcription was found to be related with the CSE inhibition of the p65/p50-driven transactivation of the COX-2 promoter.ConclusionsThe present report is first to demonstrate the anti-inflammatory activity of CSE in an in vitro cell model of joint inflammation. CSE can effectively abrogate the IL-1?-induced over-expression of inflammatory mediators at the transcriptional level in human chondrocytes and macrophages, most likely by inhibiting NF-?B (p65/p50) signaling. Blockade of IL-1?-induced NF-?B signaling and its downstream pro-inflammatory targets by CSE may be beneficial for reducing cartilage breakdown in arthritis.

Dataset Information

Immune Complex-Driven Generation of Human Macrophages with Anti-Inflammatory and Growth-Promoting Activity.

Publications

Immune Complex-Driven Generation of Human Macrophages with Anti-Inflammatory and Growth-Promoting Activity.

Similar Datasets

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